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Association between cardiovascular risk factors and coronary CT measures of coronary atherosclerosis in healthy postmenopausal women

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Association between cardiovascular risk factors and coronary CT measures of coronary atherosclerosis in healthy postmenopausal women

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ASSOCIATION BETWEEN CARDIOVASCULAR RISK FACTORS AND CORONARY
CT MEASURES OF CORONARY ATHEROSCLEROSIS IN HEALTHY
POSTMENOPAUSAL WOMEN
by
Sylvia Linda de la Rosa Pacheco

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 in Clinical, Biomedical and Translational Investigations

August 2017
ii

Table of contents
DEDICATION……………………………………………………………………..……………iii

ACKNOWLEDGMENTS………………………………………………..……………………. iv

ABSTRACT…………………………………………………………………………………...…v

BACKGROUND………………………………………...……………………………………….1

OBJECTIVE………………………………………………………………...…………..….……3

METHODS…………………………………………………………………………...…….…….4

RESULTS……………………………………………………………………………...….……...9

DISCUSSION……………………………………………………………………….…..………14

REFERENCES………………………………………………………………………………….17

TABLES AND FIGURES……………………………………………………………...………20

iii

DEDICATION
To my family, who have supported and encouraged me through everything. Thank you for your
endless love.
Colossians 3:23

iv

ACKNOWLEDGMENTS
I would like to thank my advisor, Professor Wendy Mack for all her help, patience and advice.
This work would have not been possible without her.
Professor Cecilia Patino-Sutton, my mentor through this entire journey in USC, who has thought
me invaluable life lessons.
Lastly, Professor Howard Hodis for his expertise and for letting me be part of this project.

v

ABSTRACT
Background. Atherosclerosis is the underlying cause of most cardiovascular diseases and
identification of patients at risk of cardiovascular heart disease (CHD) is an important goal in
cardiovascular medicine. Coronary CT provides measurements that can be used to screen
patients and guide clinical decisions. Coronary arterial calcification (CAC) is a known marker of
CA assessed by CT. Total plaque score (TPS) and total stenosis score (TSS) are scores that have
been used to assess the burden of CA; however, their role in the prevention, diagnosis and
treatment of CHD remains unknown.
Objective. Assess the association between cardiovascular risk factors and CT measures of CA in
healthy postmenopausal women in the Early vs. Late Intervention Trial with Estradiol (ELITE)
study.
Methods. We analyzed existing data on the participants of the ELITE study. Subjects underwent
CT scans after their last visit. We used data from the last visit and an average of these measures
during the trial, including blood pressure; lipid levels, glucose, HbAa1C, and estradiol. We
evaluated the association between cardiovascular risk factors and CT measures of CA using
logistic and linear regression.
Results. We analyzed data on 421 subjects. CAC was correlated to both TPS and TSS. TPS and
TSS also showed a high correlation. Using on-trial average measures, systolic blood pressure,
HDL, glucose and HbA1c were associated with CAC, TPS and TSS. In a multivariate analysis,
age and HDL levels were associated with CT measures after adjusting for systolic blood pressure
and glucose. Systolic blood pressure was significantly associated with TPS and TSS after
adjusting for age, HDL and glucose. Glucose association with CT measures of CA was higher
among women in early menopause compared to those in the late menopause.
vi

Discussion. This study found a significant association between CT measures of atherosclerosis
and cardiovascular risk factors. The presence of CAC is an independent predictor of
cardiovascular events; this measure was correlated to the amount of plaque (TPS) and stenosis
(TSS) present in coronary arteries. These measures of atherosclerosis showed a significant
association with cardiovascular risk factors established by the ATP III. These CT measures
might be used to detect CHD in this specific population but further studies are necessary to
validate these measures in other populations.

1

BACKGROUND:
Atherosclerosis is the underlying cause of most cardiovascular diseases. It remains as the major
cause of death and disability in developed societies despite advances in the treatment of coronary
artery disease. Many observational studies have found excess coronary risk in men compared
with premenopausal women. However, risk of coronary heart disease (CHD) accelerates in
women after menopause and after age 65 the risk equalizes for both sexes (Edmunds & Lip,
2000; Maas & Appelman, 2010).
Identification of patients at risk and prevention of CHD is an important goal in cardiovascular
medicine. New noninvasive coronary atherosclerosis (CA) imaging techniques may be useful
predictors of cardiovascular outcomes in populations at risk, and thus serve as potential
screening tools to identify healthy people at higher risk of CHD. Currently, coronary
angiography is considered the gold standard to assess CA; however, it is an invasive procedure
that provides information on the degree of stenosis but not on the extent of plaque. Therefore, a
non-invasive test to accurately diagnose CA in the general population is highly desirable
(Mowatt et al., 2008).
Coronary CT is a noninvasive imaging technique that provides images of the coronary arterial
wall and assesses the presence and extent of calcified and noncalcified atherosclerotic plaque as
well as stenosis (Munir et al., 2012; Pathan & Negishi, 2016). Atherosclerotic plaque assessment
by CT may be used as a surrogate endpoint of CHD, since atherosclerosis is the primary
underlying etiology of CHD and they both share the same pathophysiological pathway(Polak et
al., 2013). Coronary CT provides measurements that can be used to screen patients and guide
decisions about whether a more invasive and expensive intervention such as angiography is
required. However, this method still requires validation as a cardiovascular risk marker to guide
2

therapy. The accuracy of this method can be assessed by evaluating its sensitivity and specificity
using angiography as gold standard.
Coronary arterial calcification (CAC) is a known marker of CA, also assessed by CT, and is a
manifestation of atherosclerosis in asymptomatic individuals(Waugh et al., 2006). Its
relationship with cardiovascular risk factors has been established in multiple populations; (de
Vos et al., 2008) however, since not all plaques contain calcium, the absence of coronary
calcium by CT does not rule out the presence of atherosclerotic plaque (Rumberger, Simons,
Fitzpatrick, Sheedy, & Schwartz, 1995). In addition, there is no generally accepted scheme for
estimating plaque burden on coronary CT. Therefore, it is of great interest to test new tools that
can add information to the assessment of CA. CT measures of total plaque score (TPS) and total
stenosis score (TSS) are two semi-quantitative scores that take into account the area and degree
of stenosis across segments of the coronary arteries and have been used to assess the burden of
CA(Villines, 2010). However, the role of these CT measures in prevention, diagnosis and
treatment of coronary heart disease remains unknown in healthy postmenopausal women.
Risk scoring systems, like the Framingham Risk Score (FRS) and the Systematic Coronary Risk
Evaluation (SCORE) (based on age, gender, blood pressure, cholesterol levels and smoking
status), along with coronary imaging have been proposed as important tools in risk assessment;
yet, risk scoring systems have only moderate value in predicting the presence of CA (Garcia-
Lledo et al., 2016). There appears to be a significant discordance between risk factor analysis and
plaque imaging among persons with no history of heart disease (Johnson, Dowe, & Brink, 2009).
These measurements of plaque burden however, have a high degree of interobserver agreement,
suggesting a potential use in the assessment of risk of CHD (Pagali et al., 2010).

3

OBJECTIVE
As an initial validation, we aimed to assess the association between established cardiovascular
risk factors and CT measures of CA, including CAC, TPS and TSS, in healthy postmenopausal
women free of cardiovascular disease participating in the Early vs. Late Intervention Trial with
Estradiol (ELITE) study, a randomized clinical trial designed to test the hormone-timing
hypothesis in relation to atherosclerosis progression in postmenopausal women (Hodis et al.,
2016).

4

METHODS
Subjects. We analyzed existing data on the participants of the ELITE study (Hodis et al., 2016).
This trial included healthy postmenopausal women without diabetes or cardiovascular disease
who had had no regular menses for at least 6 months or who had surgically-induced menopause,
as well as a serum estradiol level lower than 25 pg/ml.
A total of 643 healthy postmenopausal women were stratified according to time since menopause
(<6 years [early post menopause] or ≥10 years [late post menopause], women 6-10 years since
menopause were excluded from the study) and were randomly assigned to receive either
hormone therapy or placebo. The primary outcome was the rate of change in carotid-artery
intima-media thickness (CIMT) which was measured every 6 months for a median of 5 years.
Secondary outcome included assessment of coronary atherosclerosis by CT, performed when
participants completed their randomly-assigned regimen. Baseline CT measures were not
obtained for the trial.
For this study, we included all consenting subjects with normal renal function (defined as
estimated glomerular filtration rate >60 ml/min/1.73 m
2
) and without known iodinated contrast
allergy, that underwent sequential non-contrast followed by contrast CT scans within 6 months
after their last clinic visit. Women who completed follow up before CT scans took place,
declined to participate in the CT assessment, or whose CT scan information was not available for
analysis were excluded from the present study and analysis. CT measurements were not obtained
from women who suffered from myocardial infarction, stroke or percutaneous coronary
intervention before the end of the trial, weighed more than 300 pounds, had uncontrolled
tachycardia or irregular heart rates (i.e., atrial fibrillation).

5

Assessment of clinical data. Clinical data were collected at each in-clinic visit, including weight,
blood pressure and pulse rate, and use of non-study medications; standardized adverse and
clinical event case report forms were completed. Age, race and education level were collected on
the first visit.
Fasting blood samples were collected for measurement of lipids, HbA1c, and other chemistries.
Estradiol levels were quantified in plasma using a specific and sensitive radioimmunoassay
(RIA) after purification, using assay methods in the University of Southern California (USC)
Reproductive Endocrine Laboratory.
In the current analysis, we used data from the last clinical visit closest to the CT scan of each
subject, including: systolic and diastolic blood pressure; total, LDL, and HDL cholesterol;
triglycerides; glucose and HbAa1C; and estradiol. The use of alcohol, smoking or any
antihypertensive medication or statins during the trial was also recorded. An average of these
measures during the trial (averaged over all visits at which these data were collected) was also
obtained for use in analyses.
CT assessment of CA. A cardiac GE 64 MDCT located at the Los Angeles Biomedical Research
Institute CT Imaging Center at Harbor-UCLA Medical Center was used to obtain the CT scan
from which measurements of CA were obtained.
Coronary artery calcium score (CAC). CAC was calculated from the non-contrast images using
standard MESA methods (Carr et al., 2005). CAC was defined as a plaque of at least 3
contiguous pixels (area 1.02 mm2) with a density of >130 HU. The lesion score was calculated
by multiplying the lesion area by a density factor derived from the maximal HU within this area.
A total CAC score was determined by summing the individual lesion scores from each of 4
anatomic sites (right coronary, left main, left anterior descending, left circumflex).
6

Total Plaque Score (TPS). Plaque area was manually traced per slice in all affected coronary
segments. The plaque area of each coronary plaque visualized in at least 2 adjacent slices
(reconstructed slice thickness 0.6 mm) was determined on all affected slices and plaque volume
assessed by multiplying the area with the slice thickness. The total plaque per segment was
summed and a semi quantitative plaque score was applied. Each plaque was multiplied by 1 for
small plaque volume, 2 for medium plaque volume and 3 for large plaque volume (Small plaque
defined as <1 mm in diameter perpendicular to the artery, medium as 1-2 mm in diameter and
large as >2 mm). TPS was determined by summing the individual plaque score over all evaluable
coronary segments (maximum plaque score = 45).
Total Stenosis Score (TSS). Segments with stenosis 1-25% diameter narrowing was defined as
having minimal stenosis, 26%-50% diameter narrowing was defined as mild stenosis, 51-75%
diameter narrowing was defined as moderate stenosis and those with >75% diameter narrowing
was defined as severe stenosis. Segment stenosis score was generated based on the degree of
underlying stenotic disease in each segment (0=no plaque, 1=1-25% stenosis, 2=26-50%
stenosis, 3=51-75% stenosis, 4=>75% stenosis). The extent scores of all 15 individual segments
were summed to yield a total score ranging from 0 to 60.
Statistical analysis. Statistical analyses were performed using Stata statistical software (Release
14. College Station, TX: Stata Corp LP.)
We evaluated the association between cardiovascular risk factors and CT measures of CA using
univariate and multivariate logistic and linear regression as appropriate to obtain odds ratio (OR),
β coefficients, 95% Confidence intervals (CI) and p values from likelihood ratio (LR), Wald and
F tests. A two-sided p-value <0.05 was considered statistically significant.
7

Cardiovascular risk factors were analyzed as dependent variables using measures obtained at the
end of trial (closest to CT measures). To reduce random measurement error, we also analyzed
risk factor measures averaged during the trial (baseline and every 6 months for a median of 5
years).
Cardiovascular risk factors including age, body mass index, estradiol levels, systolic blood
pressure and lipid levels (total cholesterol, HDL, LDL and triglycerides) were categorized using
clinical cut off values and quartiles when appropriate. Use of alcohol, HbA1c, glucose and
diastolic blood pressure variables were analyzed as dichotomous variables using normal limits by
clinical guidelines as cut-off values.
For this study, the CAC score was modeled as a dichotomous variable using cut-off values of
100 and 0. A score of 100 was reported to yield a sensitivity of 70-100% and a specificity of 87-
97% in identifying significant coronary artery stenosis in stable patients with symptoms
suggestive of CAD compared to coronary computed tomographic angiography (CCTA)
(Hanifehpour, Motevalli, Ghanaati, Shahriari, & Aliyari Ghasabeh, 2016; Ibrahim et al., 2013).
We also categorized CAC as a dichotomous variable defined as no calcium (0) vs presence of
coronary calcium (>0) since the absence of CAC has been associated with low risk of
cardiovascular events(Sarwar et al., 2009). TPS and TSS scores were analyzed as continuous
measurements.

8

RESULTS
Sample characteristics. We analyzed available data on 421 subjects [Figure 1]. In contrast to the
analysis of these data in the primary ELITE outcome paper (Hodis et al., 2016), we included: (1)
subjects that had CT scans more than 6 months after completing the study (n=9) and, (2) those
who had less than 80% adherence to the ELITE study regimen, as assessed by pill count (n=31).
One subject had only CT TPS and TSS measures (no CAC) and 6 subjects had only a CAC
measure (no TPS, TSS). We therefore analyzed a total of 420 subjects with CAC and 415
subjects with TPS and TSS measures.
Table 1 shows demographic and clinical characteristics (evaluated at the last clinic visit) of the
sample population. Continuous variables are described using mean and standard deviation as
well as median and interquartile range when appropriate. Categorical variables are described
using counts and percentages. The sample consisted of 421 healthy postmenopausal women with
a mean (SD) age of 65.7 (6.6) years, and with a mean BMI categorized as overweight (26.8 (5.5)
kg/m
2
). Mean systolic and diastolic blood pressures were in the clinically normal range, and 32%
of the women used an antihypertensive medication. Mean lipid levels including HDL, LDL and
triglycerides were all within the recommended range; the mean total cholesterol was slightly
above the recommended limit of 200 (209 mg/dL), and 31% of the population used statins. Mean
glucose and Hba1C levels were within the normal range. Estradiol levels ranged from 9 to 234
pg/ml, reflecting levels in both HT- and placebo-treated participants. Almost 70% of the women
were Caucasian and almost 93% had at least attended college.
CT measures. Table 2 presents the distribution of the CT measures analyzed. We also analyzed
the correlation between each of the measures using Spearman correlation coefficients. CAC was
9

correlated to both TPS and TSS (correlation coefficient 0.828 and 0.822 respectively). TPS and
TSS also showed a high correlation (r = 0.976).
Associations of CHD risk factors with the presence of CAC. Using values of risk variables from
the last clinic visit at the end of the trial, age was statistically significantly positively associated
with CAC, both with a cut off value of 0 and 100 (both p<0.0001). Even though fasting glucose
level was not associated with CT plaque and stenosis measures, HbA1c showed a significant
positive association with CAC (p=0.021 for cut off value of 100 and p=0.043 for cut off value of
0). HDL cholesterol levels were negatively associated with CAC with a cut off value of 0
(p=0.034) and LDL was marginally associated with CAC with a cutoff value of 100 (p=0.049);
the LDL association was lost after adjusting for statins (p=0.15). BMI, alcohol, smoking history,
systolic and diastolic blood pressure, glucose, total cholesterol, and triglycerides were not
associated with CAC [Table 3].
In the analysis using on-trial average measures, glucose and HbA1c were positively associated
with all CT measures. Averaged HDL cholesterol was associated with CAC after adjusting for
statins (p=0.007 for cut off value of 100 and p=0.02 for cut off value of 0). Systolic blood
pressure was also positively associated with the presence of CAC (p=0.021 for cut off value of
100 and p=0.039 for cut off value of 0); however, there was no association after adjusting for
antihypertensive medication (p=0.27 for cut off value off 100 and p=0.24 for a cut off value of
0). Averaged levels of BMI, diastolic blood pressure, total cholesterol, LDL cholesterol and
triglycerides were not associated with the presence of CAC [Table 4].
Associations of CHD risk factors with continuous atherosclerosis measures (TPS and TSS).
Using risk factor levels measured at the last clinic visit, age was significantly positively
associated with TPS and TSS (both p<0.0001). Alcohol was negatively associated with TPS (p =
10

0.046). HbA1c showed a significant association with TPS (p= 0.011) and TSS (p= 0.016).
Systolic blood pressure also showed a significant positive association with TPS and TSS (p=
0.027 and p=0.031); however, the association was not significant after adjusting for
antihypertensive medication (p= 0.15 and p=0.24). HDL cholesterol levels were negatively
associated with TPS (p =0.044), but the association was not significant after adjusting for statin
use (p= 0.09). LDL >160 levels were significantly positively associated with TPS compared to
levels <100 before and after adjusting for statins (p=0.040 and p=0.014 respectively). BMI,
smoking history, diastolic blood pressure, glucose, total cholesterol, and triglycerides were not
associated with CT measures [Table 3].
In the analysis using on-trial average measures, glucose and HbA1c were also positively
associated with TPS and TSS. Systolic blood pressure showed a significant positive association
with both TPS and TSS (p<0.0001), which remained significant after adjusting for
antihypertensive medication (p=0.023 and p=0.006). Averaged HDL cholesterol was also
negatively associated with TPS and TSS after adjusting for statins (p=0.011 and p=0.0021).
Trial-averaged levels of BMI, diastolic blood pressure, total cholesterol, LDL and triglycerides
were not associated with CT measures [Table 4].
Associations of estradiol levels with atherosclerosis CT measures. Estradiol levels were not
associated with any of the CT measures of atherosclerosis [Table 5]. However, using estradiol
levels measured at the last trial visit, the odds of coronary calcium tended to decrease as estradiol
levels increased. Mean TPS and TSS values also decreased as estradiol levels increased. This
trend however, was not observed for the average on trial measures of estradiol. To further
investigate this association, in light of the timing hypothesis for hormone therapy effects as a
function of time since menopause, we stratified our sample by early and late menopause. No
11

significant association between estradiol levels and CT measures of atherosclerosis were found
in either of the strata.
Multivariate analysis. Using averaged on trial cardiovascular risk factors we performed a
multivariate analysis to test their association with CT measures [Table 6]. We included age,
systolic blood pressure, HDL, glucose and HbA1C levels, which showed a statistically
significant association in the univariate analysis across all the CT measures. HbA1C was not
significantly associated with any of the CT measures after adjusting for age, systolic blood
pressure, HDL and glucose; HbA1C was therefore removed from the models.
Age and HDL levels were statistically significantly associated with all CT measures after
adjusting for systolic blood pressure and glucose (age was positively associated, whereas HDL
levels were negatively associated).
Systolic blood pressure was significantly associated with TPS and TSS (p=0.019 and 0.0073)
after adjusting for age, HDL and glucose; but showed no association with CAC (p=0.31 for a
cutoff value of 100 and 0.59 for a cutoff value of 0).
Glucose showed a positive significant association with CAC with a cutoff value of 0 (p=0.033)
and with TPS (p=0.040), but no significant association with CAC cutoff value of 100 and TSS
(p=0.060 and 0.093).
We tested if the associations of the variables included in the model were confounded by race,
education, antihypertensive medication and statins. Only antihypertensive medications showed
an important change in coefficient of average systolic blood pressure and therefore was included
in the model. After adjusting for antihypertensive medication, only age and HDL levels remained
significantly associated with CT measures [Table 7].
12

We also analyzed if the association of CT measures and cardiovascular risk factors differed by
time since menopause by adding interaction terms in the model. The interaction of glucose with
time since menopause was statistically significant in CAC with a cut off value of 100 (p=0.004),
TPS (p=0.035) and TSS (p=0.034). After adjusting for antihypertensive medication, this
interaction was significant for CAC with a cutoff value of 100 (p=0.006) but not for TPS
(p=0.069) and TSS (p=0.067). Given these results, we estimated the odds ratio and β coefficients
for women with glucose levels >100mg/dL, in early vs late menopause [Table 8 and 9]. We
found that the glucose association with CAC, TPS and TSS was higher among women in early
menopause (<6 years) compared to those in the late menopause.

13

DISCUSSION
Smoking, hypertension, low HDL cholesterol, family history of premature atherosclerotic CVD
and age >55 in women are considered the most important risk factors for CHD by the Adult
Treatment Panel III (ATP III) of the National Cholesterol Education Program (Grundy et al.,
2004). Previous studies have found that age, dyslipidemia, hypertension, diabetes and smoking
are independently predictive of coronary calcium presence in symptomatic patients.
Specifically, in women, the most important predictors of CAC are diabetes and smoking (Nicoll
et al., 2016a). Although this study excluded diabetic women, and our sample had a low
prevalence of smoking, we evaluated the association of atherosclerosis by CT with other
cardiovascular risk factors.
We found a high correlation between CAC and other CT measures of coronary atherosclerosis
(TPS and TSS), which suggest that these measures might aid in the early diagnosis of CHD in
patients that present cardiovascular risk factors. This is consistent with previous findings that
CAC score is an accurate predictor of significant coronary stenosis in symptomatic patients
(Nicoll et al., 2016b).
In our study of postmenopausal women who were free of diabetes and cardiovascular disease at
enrollment, we found a significant association between atherosclerosis CT measures and age,
systolic blood pressure, HbA1C, HDL and LDL cholesterol levels, which is consistent with the
risk factors established by the ATP III guidelines (Grundy et al., 2004). Even though our study
did not include diabetic women; the HbA1c association was significant, which suggests that
glucose metabolism is an important risk factor for CHD in this population. We did not find an
association between atherosclerosis CT measures and estradiol levels; however, the finding that
the odds of coronary calcium tended to decrease as estradiol levels increased is consistent with
14

previous findings that hormone therapy is associated with lower levels of coronary calcification
(Manson et al., 2007). Similarly, TPS and TSS values showed a similar trend, which might
suggest a similar pathophysiological pathway for stenosis and plaque.
In our multivariate analysis, we found that the association of atherosclerosis by CT measures and
glucose levels was stronger in early postmenopausal women. Although the association between
glucose, atherosclerosis and menopause has been established in previous studies (Chait &
Bornfeldt, 2009; Kim, 2012; Stuenkel, 2017), the finding that the association is most evident in
the early post menopause period has not yet been explored. It has been hypothesized that
menopause could increase glucose levels through increase in androgenicity, adiposity and insulin
resistance (Kim, 2012); in addition, the Study of Women’s Health Across the Nation (SWAN),
found that glucose levels decreased slightly but significantly with aging in premenopausal
women followed through post menopause (Janssen, Powell, Crawford, Lasley, & Sutton-Tyrrell,
2008), which might explain the findings in our study. However, the possibly time-dependent
association of glucose metabolism in postmenopausal women with the risk of atherosclerosis
should be considered in future studies.
Strengths and limitations. Our study included a large and homogeneous population of healthy
postmenopausal women. This increased our study internal validity; however, generalizability is
limited and results should be interpreted carefully when applied to different populations.
Baseline analysis on CT measures was not possible since CT was only performed at the end of
the trial, and we were not able to determine a temporal relationship between atherosclerosis CT
measures and cardiovascular risk factors.
Conclusion. This study found an association between CT measures of atherosclerosis and
individual cardiovascular risk factors. The presence of coronary calcium has been found to be an
15

independent predictor of cardiovascular events (Nicoll et al., 2016a); and we found that this
measure of atherosclerosis is highly correlated to the amount of plaque (TPS) and stenosis (TSS)
present in coronary arteries; at the same time, these measures of atherosclerosis showed a
significant association with cardiovascular risk factors established by the ATP III. These CT
measures might be used to detect CHD in this specific population but further studies are
necessary to validate these measures in other populations.

16

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hormone levels. Menopause, 19(1), 10-15. doi:10.1097/gme.0b013e318221bc8d
Nicoll, R., Wiklund, U., Zhao, Y., Diederichsen, A., Mickley, H., Ovrehus, K., . . . Henein, M.
(2016a). Gender and age effects on risk factor-based prediction of coronary artery
calcium in symptomatic patients: A Euro-CCAD study. Atherosclerosis, 252, 32-39.
doi:10.1016/j.atherosclerosis.2016.07.906
Nicoll, R., Wiklund, U., Zhao, Y., Diederichsen, A., Mickley, H., Ovrehus, K., . . . Henein, M.
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Pagali, S. R., Madaj, P., Gupta, M., Nair, S., Hamirani, Y. S., Min, J. K., . . . Budoff, M. J.
(2010). Interobserver variations of plaque severity score and segment stenosis score in
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18

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19

TABLES AND FIGURES
Figure 1. ELITE trial enrollment, randomization, follow-up and inclusion in present study

*Total sample in present study included 421 women who had a CT scan after completing the ELITE trial, we included women in early and late
menopause stratum and randomized to treatment and placebo.

643 subjects
randomized to ELITE
protocol
271 in early
menopause stratum
137 assigned
to treatment
6 adverse events
2 unable to contact
4 other reasons
125 completed
follow up
28 ended study before scan
6 declined to participate
91 had CT scan at
the end of the study
134 assigned
to placebo
1 adverse event
2 unable to contact
8 other reasons
123 completed
follow up
33 ended study before scan
4 declined to participate
3 other reason
83 had CT scan at
the end of the study
372 in late
menopause stratum
186 assigned
to treatment
6 adverse events
2 unable to contact
6 other reasons
172 completed
follow up
51 ended study before scan
5 declined to participate
1 other reason
115 had CT scan at
the end of the study
186 assigned
to placebo
3 adverse events
1 unable to contact
6 other reasons
176 completed
follow up
35 ended study before scan
6 declined to participate
3 other reasons
132 had CT scan at
the end of the study
20

Table 1. Demographic and clinical characteristics

BMI: Body mass index SBP: Systolic blood pressure DBP: Diastolic blood pressure HDL: High density lipoprotein LDL: Low density lipoprotein
Categorical variables described in frequencies and percentage, normally distributed variables in mean and standard deviation, non-normal variables as mean and interquartile range.
Variable N=421

Age (years)
Mean
65.73
SD
(6.6)
Race
White non-Hispanic
Non-Hispanic
Hispanic
Asian
N
292
37
55
37
%
(69.4)
(8.8)
(13.1)
(8.8)
Education
<8
th
grade
Some High School
High School graduate
Trade/Business
Some College
Bachelor degree
Graduate degree
N
1
2
16
12
106
124
160
%
(0.2)
(0.5)
(3.8)
(2.9)
(25.2)
(29.5)
(38)
BMI (kg/m
2
)
Average on trial
End of trial
Mean
27
26.8
SD
(5.3)
(5.5)

Use of alcohol
N
269
%
(63.9)
Smoking history
Current
Former
Never
N
21
153
247
%
(5)
(36.3)
(58.7)
Estradiol (pg/mL)
Average on trial
End of trial
Median
20.2
15
IQR
(11.3-44.7)
(9-36.5)
Time since menopause
<6 years
≥10 years
N
174
247
%
(41.3)
(58.7)
SBP (mmHg)
Average on trial
End of trial
Mean
114.9
113.4
SD
(9.7)
(11.3)
DBP (mmHg)
Average on trial
End of trial
Mean
73.3
71.4
SD
(5.4)
(7).0
Use of antihypertensive
medications
N
135
%
(32.1)
Total cholesterol (mg/dL)
Average on trial
End of trial
Mean
212.8
209.1
SD
(28.3)
(33.9)
Triglycerides (mg/dL)
Average on trial
End of trial
Median
97
94.5
IQR
(74.9-124.2)
(70-125.8)
HDL cholesterol (mg/dL)
Average on trial
End of trial
Mean
70.9
72.3
SD
(18.3)
(19.8)
LDL cholesterol (mg/dL)
Average on trial
End of trial
Mean
120.9
116
SD
(26.4)
(30)

Use of statins
N
130
%
(30.9)
Glucose (mg/dL)
Average on trial
End of trial
Mean
90.9
91.6
SD
(8.1)
(10.1)
HBa1C (%)
Average on trial
End of trial
Mean
5.8
5.7
SD
(0.36)
(0.4)
21

Table 2. Atherosclerosis distribution among CT scores
CT
measure
CAC (n=420) TPS (n=415) TSS (n=415)
Range 0-3277 0-23 0-19
Mean
(SD)
68.14(±227.51) 2.42(±3.62) 2.44(±3.50)
Category CAC
≥100
CAC >0 CAC
<100
CAC
≥100
CAC 0 CAC >0 CAC
<100
CAC
≥100
CAC 0 CAC
>0
Count
(%)
65
(15.5%)
194
(46.2%)
351
(84.8%)
63
(15.2%)
224
(54.1%)
190
(45.9%)
351
(84.8%)
63
(15.2%)
224
(54.1%)
190
(45.9%)
Mean
(SD)
NA NA 1.37
(±1.99)
8.3
(±4.88)
0.46
(±0.99)
4.7
(±4.19)
1.44
(±2.09)
8.03
(±4.41)
0.45
(±0.92)
4.8
(±3.94)
Median NA NA 1.00 7.00 0 4.00 1.00 7.00 0 4.00

NA Not applicable
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions.
*One subject had only CT TPS and TSS measures (no CAC) and 6 subjects had only a CAC measure (no TPS, TSS).

22

Table 3. Univariate regression of CT measures on cardiovascular risk factors at the end of trial
Variable

CAC* (0-99, ≥100)
OR (95%CI) p
[N=420]
CAC* (0, >0)
OR (95%CI) p
[N=420]
TPSϯ
β (95% CI) p
[N=415]
TSSϯ
β (95% CI) p
[N=415]
Age (years)
<64
65-74
>75
p value‡

1
3.02(1.5-6.03)0.002
9.27(4.02-21.4)<0.001
<0.001

1
2.8(1.8-4.2) <0.001
8.32(3.8-18) <0.001
<0.001

0
1.58(0.87-2.28) <0.001
3.48(2.33-4.62) <0.001
<0.001

0
1.54(0.87-2.21) <0.001
3.87(2.78-4.96) <0.001
<0.001

BMI (kg/m
2
)
Normal-Underweight
Overweight
Obese
p value

1
0.81(0.43-1.5)0.51
0.86(0.44-1.6)0.67
0.79

1
1.2(0.78-1.9) 0.37
1.3(0.85-2.2) 0.19
0.39

0
0.37(-0.43-1.18)0.37
0.36(-0.52-1.25)0.42
0.59

0
0.39(-0.38-1.17)0.32
0.29(-0.55-1.15)0.49
0.59
Alcohol
No
Yes

1
1.45(0.81-2.58)0.21

1
1.0(0.67-1.5)0.97

0
0.73(0.01-1.46)0.046

0
0.67(-0.02-1.37)0.06

Smoking
Never
Former
Current
p value

1
0.96(0.55-1.69)0.91
1.28(0.41-4.03)0.66
0.89

1
1.18(0.79-1.78)0.40
0.92(0.37-2.28)0.87
0.67

0
-0.17(-0.91-0.56)0.64
0.54(-1.07-2.16)0.51
0.68

0
0.04(-0.67-0.75)0.91
0.10(-1.46-1.67)0.89
0.99

Glucose (mg/dL)
Normal
>100

1
1.49(0.75-2.9)0.25

1
1.03(0.6-1.7) 0.91

0
0.46(-0.51-1.45)0.35

0
0.38(-0.56-1.34)0.42

HBa1C (%)
<6
6-8

1
2.17(1.12-4.2)0.021

1
1.78(1.01-3.13) 0.043

0
1.3(0.29-2.31)0.011

0
1.19(0.22-2.17)0.016

Estradiol (pg/ml)
≤11
12-24
25-46
≥47
p value

Adjusted for early
vs late menopause
≤11
12-24
25-46
≥47
p value

1
0.84(0.44-1.60)0.61
0.72(0.32-1.60)0.43
0.63(0.28-1.43)0.27
0.69

1
0.84(0.43-1.60)0.60
0.80(0.36-1.80)0.60
0.62(0.27-1.42)0.27
0.72

1
1.05(0.65-1.70)0.82
0.93(0.53-1.64)0.81
1.13(0.64-1.98)0.66
0.94

1
1.05(0.65-1.71)0.83
1.01(0.57-1.81)0.95
1.13(0.64-2.01)0.66
0.98

0
-0.21(-1.08-0.65)0.62
-0.61(-1.64-0.41)0.2
-0.75(-1.77-0.26)0.15
0.43

0
-0.23(-1.09-0.62)0.59
-0.45(-1.47-0.56)0.38
-0.73(-1.74-0.26)0.15
0.52

0
-0.27(-1.11-0.56)0.52
-0.60(-1.60-0.38)0.23
-0.59(-1.58-0.38)0.23
0.54

0
-0.28(-1.11-0.53)0.49
-0.43(-1.41-0.54)0.38
-0.57(-1.54-0.38)0.24
0.65
SBP (mmHg)
<106
106-112
113-119
≥120
p value

Adjusted for BP
meds
<106
106-112

1
1.19(0.55-2.56)0.64
1.40(0.63-3.08)0.40
0.81(0.37-1.74)0.59
0.51

1
0.85(0.38-1.90)0.71

1
1.11(0.63-1.96)0.69
1.18(0.64-2.14)0.59
1.56(0.92-2.65)0.096
0.35

1
0.99(0.56-1.76)0.99

0
-0.09(-1.09-0.91)0.85
0.64(-0.42-1.71)0.24
1.15(0.20-2.09)0.017
0.027

0
-0.52(-1.51-0.46)0.29

0
0.16(-0.80-1.14)0.73
0.72(-0.30-1.76)0.17
1.22(0.30-2.13)0.009
0.031

0
-0.24(1.19-0.71)0.62
23

113-119
≥120
p value

1.06(0.46-2.41)0.89
0.47(0.21-1.08)0.079
0.15
1.07(0.58-1.96)0.83
1.31(0.75-2.27)0.33
0.69
0.30(-0.74-1.34)0.57
0.48(-0.45-1.43)0.31
0.15
0.40(-0.60-1.41)0.43
0.59(-0.32-1.51)0.20
0.24
DBP (mmHg)
≤80
>80

Adjusted for BP
meds
≤80
>80

1
1.4(0.58-3.37)0.44

1
1.06(0.43-2.63) 0.89

1
1.10(0.55-2.21) 0.77

1
0.95(0.47-1.9) 0.91

0
0.82(-0.43.2.07)0.20

0
0.31(-0.91-1.53)0.62

0
0.36(-0.85-1.59)0.56

0
-0.13(-1.31-1.05)0.83

Total cholesterol
(mg/dL)
<200
200-239
≥240
p value

Adjusted for
statins
<200
200-239
≥240
p value

1
0.57(0.32-1.04)0.07
0.58(0.27-1.25)0.17
0.14

1
0.71(0.38-1.30)0.27
0.62(0.28-1.36)0.24
0.38

1
0.84(0.55-1.29) 0.43
0.73(0.42-1.26) 0.26
0.49

1
0.99(0.63-1.54) 0.97
0.77(0.44-1.35) 0.38
0.63

0
-0.23(-1.01-0.54)0.55
-0.11(-0.11-0.86)0.82
0.84

0
0.14(-0.63-0.92)0.72
0.03(-0.93-0.99)0.95
0.93

0
-0.31(-1.06-0.43)0.41
-0.006(-0.95-0.94)0.99
0.67

0
0.05(-0.70-0.80)0.89
0.13(-0.79-1.06)0.77
0.93
HDL cholesterol
(mg/dL)
<57
57-69
70-84
≥85
p value

Adjusted for
statins
<57
57-69
70-84
≥85
p value

1
0.51(0.24-1.07)0.077
0.49(0.23-1.05)0.070
0.60(0.29-1.24)0.17
0.21

1
0.51(0.24-1.09)0.083
0.52(0.24-1.11)0.095
0.68(0.32-1.40)0.29
0.12

1
0.57(0.33-1.00)0.050
0.46(0.26-0.80)0.007
0.52(0.30-0.91)0.022
0.034

1
0.57(0.33-1.00)0.054
0.47(0.26-0.83)0.010
0.56(0.32-0.98)0.044
0.032

0
-0.67(-1.66-0.31)0.180
-1.37(-2.38- -0.36)0.008
-1.08(-2.08- -0.09)0.032
0.044

0
-0.62(-1.59-0.35)0.21
-1.25(-2.23- -0.26)0.013
-0.88(-1.85-0.09)0.078
0.090

0
-0.33(-1.29-0.62)0.49
-1.16(-2.14- -0.19)0.019
-0.79(-1.75-0.16)0.103
0.089

0
-0.27(-1.21-0.66)0.56
-1.04(-2.00- -0.08)0.032
-0.59(-1.54-0.35)0.22
0.162
LDL cholesterol
(mg/dL)
<100
100-129
130-159
≥160
p value

Adjusted for
statins
<100
100-129
130-159
≥160
p value

1
0.70(0.38-1.31)0.28
0.35(0.15-0.82)0.016
1.15(0.47-2.82)0.75
0.049

1
0.89(0.47-1.71)0.75
0.44(0.18-1.04)0.062
1.32(0.53-3.30)0.55
0.15

1
1.29(0.80-2.06)0.28
0.78(0.46-1.33)0.37
1.57(0.74-3.30)0.23
0.16

1
1.62(0.98-2.65)0.055
0.96(0.55-1.67)0.89
1.80(0.84-3.86)0.13
0.083

0
0.15(-0.69-0.99)0.72
-0.47(-1.42-0.47)0.32
1.39(0.06-2.73)0.040
0.066

0
0.59(-0.25-1.44)0.170
-0.05(-1.00-0.80)0.92
1.64(0.33-2.95)0.014
0.046

0
-0.02(-0.84-0.79)0.95
-0.43(-1.35-0.48)0.35
1.28(-0.005-2.57)0.051
0.094

0
0.39(-0.42-1.22)0.34
-0.03(-0.94-0.88)0.95
1.51(0.25-2.78)0.019
0.087
Triglycerides
(mg/dL)
<70
70-94.49

1
1.11(0.53-2.32)0.78

1
0.75(0.43-1.29)0.31

0
-0.36(-1.35-0.61)0.46

0
-0.40(-1.36-0.54)0.40
24

94.5-125.74
≥125.75
p value

Adjusted for
statins
<70
70-94.49
94.5-125.74
≥125.75
p value

0.70(0.31-1.56)0.39
1.18(0.57-2.46)0.64
0.56

1
1.01(0.48-2.15)0.96
0.60(0.26-1.36)0.22
0.91(0.42-1.94)0.82
0.35
0.85(0.49-1.48)0.59
1.06(0.61-1.82)0.83
0.59

1
0.70(0.40-1.22)0.22
0.77(0.44-1.35)0.37
0.88(0.50-1.54)0.66
0.87
-0.26(-1.25-0.73)0.60
0.69(-0.30-1.68)0.17
0.14

0
-0.48(-1.45-0.48)0.33
-0.46(-1.44-0.51)0.35
0.30(-0.68-1.29)0.54
0.30
-0.07(-1.03-0.87)0.87
0.62(-0.33-1.58)0.20
0.19

0
-0.52(-1.45-0.41)0.28
-0.27(-1.22-0.66)0.57
0.25(-0.70-1.20)0.61
0.39
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions. One subject had only CT TPS and TSS
measures (no CAC) and 6 subjects had only a CAC measure (no TPS, TSS).
BMI: Body mass index SBP: Systolic blood pressure DBP: Diastolic blood pressure HDL: High density lipoprotein LDL: Low density lipoprotein
*Logistic regression
ϯ Linear regression
‡ Overall test of association p values. CAC from LR test, TPS and TSS from F tests

25

Table 4. Univariate regression of CT measures on cardiovascular risk factors (average on trial
measures)
Variable CAC* (0-99, ≥100)
OR (95%CI) p
[N=420]
CAC* (0, >0)
OR (95%CI) p
[N=420]
TPSϯ
β (95% CI) p
[N=415]
TSSϯ
β (95% CI) p
[N=415]
BMI (kg/m
2
)
Normal-Underweight
Overweight
Obese
p value ‡

1
0.92(0.49-1.71)0.79
1.16(0.60-2.26)0.65
0.79

1
1.32(0.85-2.06)0.21
1.51(0.92-2.49)0.099
0.22

0
0.44(-0.36-1.24)0.28
0.86(-0.04-1.76)0.062
0.17

0
0.67(-0.09-1.45)0.085
0.83(-0.03-1.70)0.061
0.10
Glucose (mg/dL)
Normal
>100

1
2.21(1.10-4.45)0.026

1
2.19(1.18-4.06)0.012

0
1.47(0.37-2.56)0.009

0
1.23(0.17-2.29)0.023

HBa1C (%)
<6
6-8

1
1.71(0.94-3.10)0.077

1
1.62(1.00-2.60)0.046

0
1.18(0.33-1.04)0.007

0
1.14(0.32-1.97)0.007
Estradiol (pg/ml)
≤11
12-24
25-46
≥47
p value

Adjusted for early
vs late menopause
≤11
12-24
25-46
≥47
p value

1
0.96(0.47-1.95)0.93
0.95(0.45-2.00)0.91
0.79(0.37-1.71)0.57
0.94

1
0.94(0.46-1.92)0.87
0.96(0.45-2.03)0.92
0.83(0.38-1.81)0.65
0.98

1
0.94(0.56-1.58)0.83
1.26(0.73-2.18)0.39
0.92(0.53-1.59)0.78
0.68

1
0.92(0.54-1.56)0.77
1.28(0.73-2.22)0.38
0.96(0.55-1.67)0.89
0.67

0
-0.28(-1.23-0.67)0.56
0.00(-0.98-0.98)0.99
-0.62(-1.61-0.35)0.21
0.66

0
-0.33(-1.26-0.60)0.49
0.01(-0.96-0.98)0.98
-0.54(-1.51-0.42)0.27
0.63

0
-0.21(-1.13-0.70)0.64
0.10(-0.84-1.06)0.82
-0.57(-1.52-0.37)0.24
0.54

0
-0.27(-1.17-0.63)0.55
0.12(-0.81-1.06)0.79
-0.48(-1.41-0.45)0.31
0.60

SBP (mmHg)
<106
106-112
113-119
≥120
p value

Adjusted BP meds
<106
106-112
113-119
≥120
p value

1
3.29(1.06-10.2)0.039
4.04(1.32-12.3)0.014
4.27(1.42-12.8)0.010
0.021

1
2.52(0.79-7.97)0.12
2.83(0.89-8.91)0.075
2.44(0.76-7.78)0.13
0.27

1
1.25(0.68-2.29)0.46
1.84(1.01-3.37)0.045
2.09(1.16-3.76)0.013
0.039

1
1.13(0.61-2.10)0.68
1.61(0.87-2.99)0.13
1.67(0.89-3.13)0.11
0.24

0
0.94(-0.09-1.98)0.074
1.74(0.69-2.79)0.001
2.34(1.33-3.35) <0.001
<0.0001

0
0.58(-0.44-1.61)0.27
1.22(0.17-2.27)0.023
1.51(0.45-2.57)0.005
0.023

0
0.99(-0.004-1.9)0.051
1.58(0.58-2.59)0.002
2.49(1.52-3.46) <0.001
<0.0001

0
0.65(-0.33-1.64)0.19
1.11(0.09-2.12)0.032
1.73(0.71-2.75)0.001
0.006
DBP (mmHg)
≤80
>80

Adjusted for BP
meds
≤80
>80

1
0.90(0.36-2.23)0.82

1
0.61(0.23-1.56)0.31

1
0.86(0.45-1.63)0.65

1
0.70(0.36-1.36)0.29

0
-0.14(-1.30-1.01)0.80

0
-0.76(-1.89-0.36)0.19

0
0.14(-0.97-1.26)0.79

0
-0.43(-1.53-0.66)0.44
Total cholesterol
(mg/dL)
<200
200-239

1
0.65(0.36-1.17)0.16

1
1.21(0.79-1.87)0.37

0
0.23(-0.55-1.01)0.56

0
0.16(-0.58-0.92)0.67
26

≥240
p value

Adjusted for statins
<200
200-239
≥240
p value

0.76(0.34-1.69)0.51
0.37

1
0.78(0.43-1.43)0.43
0.82(0.36-1.85)0.64
0. 73
1.17(0.64-2.11)0.60
0.66

1
1.43(0.91-2.24)0.12
1.26(0.69-2.31)0.44
0.29
0.46(-0.61-1.53)0.39
0.68

0
0.54(-0.22-1.32)0.17
0.60(-0.45-1.65)0.26
0.33
0.65(-0.37-1.69)0.21
0.46

0
0.47(-0.27-1.22)0.22
0.79(-0.22-1.80)0.13
0.26
HDL cholesterol
(mg/dL)
<57
57-69
70-84
≥85
p value

Adjusted for statins
<57
57-69
70-84
≥85
p value

1
0.79(0.40-1.54)0.49
0.23(0.09-0.59)0.002
0.73(0.34-1.58)0.44
0.005

1
0.78(0.39-1.54)0.48
0.24(0.09-0.62)0.003
0.88(0.40-1.95)0.77
0.007

1
0.76(0.44-1.30)0.32
0.40(0.22-0.71)0.002
0.52(0.28-0.96)0.038
0.008

1
0.75(0.43-1.30)0.32
0.42(0.23-0.75)0.003
0.58(0.31-1.09)0.091
0.020

0
-0.40(-1.37-0.56)0.41
-1.70(-2.72- -0.69)0.001
-0.94(-2.03-0.14)0.089
0.004

0
-0.39(-1.34-0.56)0.42
-1.56(-2.56- -0.57)0.002
-0.64(-1.72-0.43)0.24
0.011

0
-0.23(-1.17-0.70)0.63
-1.49(-2.46- -0.51)0.003
-0.77(-1.83-0.27)0.15
0.009

0
-0.21(-1.14-0.70)0.64
-1.35(-2.31- -0.39)0.006
-0.48(-1.53-0.55)0.36
0.021
LDL cholesterol
(mg/dL)
<100
100-129
130-159
≥160
p value

Adjusted for statins
<100
100-129
130-159
≥160
p value

1
1.01(0.52-1.97)0.97
0.58(0.26-1.28)0.18
1.00(0.33-3.02)0.99
0.40

1
1.07(0.54-2.11)0.83
0.70(0.31-1.57)0.39
0.94(0.30-2.90)0.93
0.68

1
1.23(0.74-2.05)0.41
1.21(0.70-2.09)0.49
1.48(0.64-3.42)0.36
0.77

1
1.30(0.78-2.18)0.31
1.41(0.80-2.48)0.22
1.43(0.61-3.36)0.41
0.63

0
0.86(-0.05-1.77)0.065
0.69(-0.29-1.68)0.17
1.19(-0.32-2.70)0.12
0.24

0
0.95(0.05-1.84)0.037
1.01(0.03-1.98)0.043
1.07(-0.40-2.55)0.15
0. 14

0
0.51(-0.36-1.40)0.25
0.57(-0.38-1.53)0.24
1.42(-0.03-2.88)0.057
0.27

0
0.60(-0.26-1.46)0.17
0.87(-0.07-1.81)0.070
1.31(-0.11-2.74)0.072
0.19
Triglycerides
(mg/dL)
<70
70-94.49
94.5-125.74
≥125.75
p value

Adjusted for statins
<70
70-94.49
94.5-125.74
≥125.75
p value

1
2.44(0.99-5.96)0.050
1.68(0.66-4.26)0.27
1.63(0.62-4.22)0.31
0.22

1
2.26(0.91-5.6)0.076
1.36(0.53-3.52)0.52
1.11(0.41-2.99)0.83
0.15

1
1.30(0.73-2.34)0.37
1.20(0.66-2.15)0.54
1.49(0.81-2.73)0.19
0.61

1
1.24(0.68-2.24)0.47
1.05(0.57-1.91)0.87
1.17(0.62-2.20)0.62
0.87

0
1.06(0.01-2.11)0.047
1.10(0.04-2.16)0.041
0.99(-0.09-2.08)0.074
0.16

0
0.93(-0.09-1.97)0.074
0.80(-0.24-1.84)0.13
0.44(-0.65-1.54)0.43
0. 29

0
0.81(-0.20-1.82)0.12
0.99(-0.02-2.02)0.055
0.82(-0.22-1.87)0.12
0.26

0
0.68(-0.30-1.68)0.18
0.70(-0.30-1.71)0.17
0.29(-0.76-1.35)0.59
0.44
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions. One subject had only CT TPS and TSS
measures (no CAC) and 6 subjects had only a CAC measure (no TPS, TSS).
BMI: Body mass index SBP: Systolic blood pressure DBP: Diastolic blood pressure HDL: High density lipoprotein LDL: Low density lipoprotein
*Logistic regression
ϯ Linear regression
‡ Overall test of association p values. CAC from LR test, TPS and TSS from F tests

27

Table 5. Univariate regression of CT measures on estradiol levels by menopause strata
Estradiol levels
(pg/ml)
CAC* (0-99, ≥100)
OR (95%CI) p
[N=420]
CAC* (0, >0)
OR (95%CI) p
[N=420]
TPSϯ
β (95% CI) p
[N=415]
TSSϯ
β (95% CI) p
[N=415]
Early menopause
(N=174)
≤11
12-24
25-46
≥47
p value ‡

LR p value
1
1.80(0.47-6.80)0.38
0.75(0.13-4.35)0.76
0.98(0.16-5.70)0.98
0.69

LR p value
1
1.03(0.46-2.30)0.94
1.21(0.51-2.88)0.66
1.22(0.48-3.09)0.67
0.96

F p value
0
0.27(-0.82-1.38)0.62
-0.40(-1.59-0.78)0.49
-0.14(-1.41-1.12)0.82
0.73

F p value
0
0.21(-0.86-1.28)0.69
-0.37(-1.52-0.78)0.53
-0.07(-1.31-1.15)0.90
0.81
Late menopause
(N=247)
≤11
12-24
25-46
≥47
p value

1
0.65(0.30-1.39)0.27
0.85(0.34-2.15)0.74
0.55(0.21-1.41)0.22
0.54

1
1.07(0.58-1.97)0.82
0.87(0.40-1.89)0.73
1.09(0.52-2.24)0.81
0.96

0
0.55(-1.78-0.67)0.38
-0.40(-1.98-1.17)0.62
-1.12(-2.59-0.33)0.13
0.49

0
-0.60(-1.78-0.57)0.32
-0.40(-1.92-1.10)0.59
-0.91(-2.31-0.48)0.20
0.59
Early menopause
(average on trial)
≤11
12-24
25-46
≥47
p value

1
1.10(0.25-4.71)0.89
1.22(0.28-5.26)0.78
0.51(0.08-2.94)0.45
0.75

1
1.02(0.42-2.49)0.95
2.02(0.84-4.87)0.12
0.89(0.36-2.18)0.81
0.26

0
0.40(-0.79-1.61)0.50
0.30(-0.90-1.51)0.62
-0.52(-1.69-0.63)0.37
0.42

0
0.15(-1.02-1.32)0.79
0.07(-1.10-1.24)0.91
-0.63(-1.76-0.49)0.27
0.53
Late menopause
(average on trial)
≤11
12-24
25-46
≥47
p value

1
0.90(0.39-2.04)0.80
0.88(0.36-2.10)0.77
0.96(0.40-2.32)0.94
0.99

1
0.86(0.44-1.68)0.67
0.94(0.46-1.91)0.87
1.02(0.49-2.12)0.94
0.96

0
-0.78(-2.12-0.56)0.25
-0.18(-1.61-1.24)0.79
-0.50(-1.97-0.95)0.49
0.69

0
-0.52(-1.81-0.77)0.43
0.16(-1.21-1.53)0.82
-0.34(-1.74-1.06)0.63
0.75
One subject had only CT TPS and TSS measures (no CAC) and 6 subjects had only a CAC measure (no TPS, TSS).
* Logistic regression
ϯ Linear regression
‡ Overall test of association p values. CAC from LR test, TPS and TSS from F tests

28

Table 6. Multivariate regression of CT measures on cardiovascular risk factors (average on trial
measures)
Variable CAC* (0-99, ≥100)
OR (95%CI) p
[N=420]
CAC* (0, >0)
OR (95%CI) p
[N=420]
TPSϯ
β (95% CI) p
[N=415]
TSSϯ
β (95% CI) p
[N=415]
Model p value <0.0001 <0.0001 <0.0001 <0.0001

Age years
<64
65-74
>75
p value‡

1
2.76(1.36-5.60)0.005
9.88(4.04-24.1) <0.001
<0.0001

1
2.69(1.73-4.19) <0.001
9.23(4.13-20.6) <0.001
<0.0001

0
1.31(0.61-2.01) <0.001
3.26(2.13-4.40) <0.001
<0.0001

0
1.27(0.60-1.93) <0.001
3.60(2.52-4.69) <0.001
<0.0001
SBP (mmHg)
<106
106-112
113-119
≥120
p value‡

1
2.38(0.73-7.68)0.15
2.81(0.87-9.0)0.082
2.32(0.73-7.37)0.15
0.307

1
0.92(0.48-1.76)0.81
1.35(0.70-2.58)0.36
1.15(0.60-2.19)0.67
0.595

0
0.47(-0.51-1.47) 0.35
1.24(0.22-2.25) 0.016
1.39(0.38-2.40) 0.007
0.0198

0
0.53(-0.41-1.48) 0.27
1.08(0.12-2.05) 0.027
1.58(0.62-2.54) 0.001
0.0073
HDL (mg/dL)
<57
57-69
70-84
≥85
p value‡

1
0.69(0.33-1.44)0.33
0.21(0.08-0.57)0.002
0.78(0.33-1.85)0.59
0.0065

1
0.74(0.41-1.32)0.32
0.40(0.21-0.74)0.004
0.57(0.29-1.11)0.101
0.0228

0
-0.28(-1.21-0.64) 0.55
-1.44(-2.41- -0.47)0.004
-0.52(-1.58-0.54) 0.34
0.0139

0
-0.12(-1.01-0.75) 0.78
-1.23(-2.16- -0.31)0.009
-0.40(-1.41 -0.61) 0.44
0.023
Glucose
(mg/dL)
Normal
>100

1
2.09(0.97-4.54)0.060

1
2.07(1.05-4.05)0.033

0
1.1(0.04-2.16) 0.040

0
0.86(-0.14-1.86) 0.093
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions. One subject had only CT TPS and TSS
measures (no CAC) and 6 subjects had only a CAC measure (no TPS, TSS).
SBP: Systolic blood pressure DBP: HDL: High density lipoprotein
* Logistic regression
ϯ Linear regression
‡ Overall test of association p values. CAC from LR test, TPS and TSS from F tests

29

Table 7. Multivariate regression of CT measures on cardiovascular risk factors adjusted for
antihypertensive medication (average on trial measures)
Variable CAC* (0-99, ≥100)
OR (95%CI) p
[N=420]
CAC* (0, >0)
OR (95%CI) p
[N=420]
TPSϯ
β (95% CI) p
[N=415]
TSSϯ
β (95% CI) p
[N=415]
Model p value <0.0001 <0.0001 <0.0001 <0.0001
Age years
<64
65-74
>75
p value‡

1
2.63(1.28-5.39)0.008
9.82(3.95-24.4) <0.001
<0.0001

1
2.65(1.70-4.12) <0.001
9.31(4.15-20.8) <0.001
<0.0001

0
1.22(0.54-1.91) <0.001
3.22(2.11-4.34) <0.001
<0.0001

0
1.19(0.53-1.85) <0.001
3.56(2.50-4.63) <0.001
<0.0001
SBP (mmHg)
<106
106-112
113-119
≥120
p value‡

1
1.85(0.54-6.11)0.31
2.06(0.62-6.81)0.23
1.39(0.41-4.74)0.59
0.51

1
0.85(0.44-1.65)0.65
1.23(0.63-2.38)0.54
0.98(0.49-1.94)0.96
0.67

0
0.19(-0.79-1.18)0.69
0.82(-0.19-1.84)0.11
0.74(-0.29-1.79)0.16
0.29

0
0.27(-0.67-1.21)0.57
0.70(-0.27-1.67)0.16
0.98(-0.01-1.97)0.054
0.19
HDL (mg/dL)
<57
57-69
70-84
≥85
p value‡

1
0.68(0.32-1.44)0.32
0.24(0.09-0.65)0.005
0.83(0.34-1.99)0.68
0.016

1
0.74(0.41-1.32)0.31
0.40(0.21-0.75)0.004
0.57(0.29-1.12)0.11
0.027

0
-0.29(-1.20-0.62)0.53
-1.34(-2.3- -0.39)0.006
-0.47(-1.51-0.57)0.38
0.024

0
-0.13(-1-0.73)0.77
-1.14(-2.06- -0.23)0.014
-0.35(-1.34-0.64)0.48
0.039
Glucose
(mg/dL)
Normal
>100

1
1.87(0.84-4.14)0.122

1
1.97(1-3.88)0.047

0
0.86(-0.81-1.90)0.105

0
0.63(-0.36-1.63)0.21

Blood pressure
medications

2.48(1.32-4.65)0.004

1.4(0.87-2.26)0.16

1.47(0.72-2.21) <0.001

1.36(0.65-2.07) <0.001
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions.
SBP: Systolic blood pressure DBP: HDL: High density lipoprotein
* Logistic regression
ϯ Linear regression
‡ Overall test of association p values. CAC from LR test, TPS and TSS from F tests

30

Table 8. Interaction analysis of glucose by time since menopause adjusted for age, systolic blood pressure
and HDL levels
Variable OR for CAC /
β for TPS, TSS
95% CI p value
CAC* (0-99, ≥100)

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

9.79
0.90

2.78-34.45
0.32-2.50

<0.0001
0.841
CAC* (0, >0)

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

2.84
1.63

1.03-7.79
0.68-3.88

0.042
0.266
TPSϯ

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

2.44
0.20

0.81-4.07
-1.14-1.54

0.003
0.768
TSSϯ

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

2.14
-0.005

0.58-3.69
-1.28-1.27

0.007
0.994
CAC measured in Agatston units. TPS and TSS Scores measured according to authors definitions. Glucose measured in mg/dL
* Logistic regression
ϯ Linear regression

31

Table 9. Interaction analysis of glucose by time since menopause adjusted for age, systolic blood
pressure, antihypertensive medication and HDL levels
Variable OR for CAC /
β for TPS, TSS
95% CI p value
CAC* (0-99, ≥100)

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

8.05
0.81

2.24-28.92
0.28-2.33

0.001
0.696
CAC* (0, >0)

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

2.63
1.60

0.94-7.28
0.67-3.83

0.063
0.283
TPSϯ

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

2.00
0.10

0.39-3.63
-1.22-1.42

0.015
0.881
TSSϯ

Glucose >100, menopause < 6 years
Glucose >100, menopause > 10 years

1.73
-0.10

0.19-3.28
-1.36-1.16

0.028
0.878
* Logistic regression
ϯ Linear regression

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Asset Metadata

Creator de la Rosa Pacheco, Sylvia Linda (author)

Core Title Association between cardiovascular risk factors and coronary CT measures of coronary atherosclerosis in healthy postmenopausal women

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 06/05/2017

Defense Date 08/08/2017

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag atherosclerosis,cardiovascular,coronary,CT,factors,OAI-PMH Harvest,postmenopausal,risk,Women

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Hodis, Howard (committee chair), Mack, Wendy (committee member), Patino-Sutton, Cecilia (committee member)

Creator Email sldelaro@usc.edu,sylvia-delarosa@hotmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-379090

Unique identifier UC11258143

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Legacy Identifier etd-delaRosaPa-5374.pdf

Dmrecord 379090

Document Type Thesis

Rights de la Rosa Pacheco, Sylvia Linda

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA