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Association of arterial stiffness progression with subclinical atherosclerosis measurements in postmenopausal women

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Association of arterial stiffness progression with subclinical atherosclerosis measurements in postmenopausal women

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ASSOCIATION OF ARTERIAL STIFFNESS PROGRESSION WITH SUBCLINICAL
ATHEROSCLEROSIS MEASUREMENTS IN POSTMENOPAUSAL WOMEN

By
Ziyu Jin

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)

DECEMBER 2023

Copyright 2023 Ziyu Jin

ii
Table of Contents
List of Tables ............................................................................................................................... iii
Abstract ....................................................................................................................................... iv
Chapter 1: Introduction ................................................................................................................ 1
Chapter 2: Methods …………………………………………………………….....….………………... 4
Study Design ……………………………………………….…..………..………………...………. 4
Randomization and Treatment …………………………...………..…………………………...... 4
Participant Follow-up during the Trial ……………………...……...…………………….….…… 5
Common Carotid Artery Ultrasonogram ………...…………………..……………………....….. 6
Statistical Analysis ………………………………………………………...……………..………... 7
Chapter 3: Results …………………………………………………………………………………….. 10
Baseline Characteristics …………………..…………………………………………………….. 10
Baseline Correlation Between CIMT, IM-GSM, and Arterial Stiffness
Measures…………………………...…………………………………………………..…………. 11
Risk Factors of Arterial Stiffness ……..………………………..…………………………….…. 12
Association Between Subclinical Atherosclerosis and Arterial Stiffness
Progression …..……………………………………………………………………….………….. 14
Association Between IM-GSM and Arterial Stiffness Progression ….………………..…….. 15
Association Between CIMT and Artery Stiffness Progression …………………………….… 16
Chapter 4: Discussion ……………………………………………………..…………………………. 18
References ……………………….……………………………………………...………………...….. 21

iii

List of Tables
TABLE 1. DEMOGRAPHIC AND CLINICAL VARIABLES (N=596) ............................................ 11
TABLE 2. CORRELATION MATRIX OF THE ATHEROSCLEROSIS MEASURES .................... 12
TABLE 3. UNADJUSTED ASSOCIATION OF CARDIOVASCULAR RISK FACTORS
WITH ARTERIAL STIFFNESS MEASURES ............................................................................... 13
TABLE 4. MULTIVARIABLE ASSOCIATION OF CARDIOVASCULAR RISK FACTORS
WITH ARTERIAL STIFFNESS MEASURES AT BASELINE ....................................................... 14
TABLE 5. THE ASSOCIATION OF BASELINE ATHEROSCLEROSIS WITH ARTERIAL
STIFFNESS PROGRESSION .................................................................................................... 14
TABLE 5A. THE ASSOCIATION OF BASELINE IM-GSM WITH ARTERIAL
STIFFNESS PROGRESSION BY TREATMENT GROUP, ANTIHYPERLIPIDEMIC
USE, POSTMENOPAUSE STRATUM ........................................................................................ 15
TABLE 5B. THE ASSOCIATION OF BASELINE CIMT WITH ARTERIAL
STIFFNESS PROGRESSION BY TREATMENT GROUP,
ANTIHYPERLIPIDEMIC USE, POSTMENOPAUSE STRATUM .............................................. 17

iv
Abstract
Objectives: To evaluate whether atherosclerosis is associated with arterial stiffness progression.
Background: Subclinical atherosclerosis can be assessed by ultrasound measurement of carotid
artery intima-media thickness and gray-scale median of the intima-media complex. An association
between arterial stiffness and atherosclerosis has been observed in many studies. We
hypothesized that atherosclerosis is a precursor of arterial stiffness.
Methods: 643 healthy postmenopausal women, who were participants in the Early vs. Late
Intervention Trial with Estradiol (ELITE), were included in the analyses. Carotid intima-media
thickness, gray-scale median of the intima-media complex, and arterial stiffness were measured
by B-mode ultrasonogram. Linear mixed effect models included baseline measures of carotid
intima-media thickness and gray-scale median of the intima-media complex as exposure
variables and longitudinal measures of arterial compliance and arterial distensibility measured
over 5 years as outcome variables. Further analyses were stratified by lipid-lowering medication
use, randomization group, and postmenopausal group defined by time since menopause (<6
years, ≥10 years).
Results: Overall, there was no significant association between atherosclerosis and arterial
stiffness progression (p>0.05). Associations were also not apparent in subgroups defined by lipid-
lowering, randomization group, or time since menopause group.
Conclusions: Levels of subclinical atherosclerosis do not relate to subsequent progression of
v

carotid artery stiffness.

1
Introduction
According to the World Health Organization, cardiovascular disease (CVD) is the third leading
cause of death among adults in industrialized countries.
1
Atherosclerosis is the most common
pathophysiologic etiology for CVD.
1
Atherosclerosis is a chronic immunoinflammatory disease,
which involves interactions between modified lipoproteins, monocyte-derived macrophages, T
cells, and vascular tissue, leading to the thickening of the arterial wall.
2
Development and
progression of plaques or complex lesions can intrude into the arterial lumen as a result of this
inflammatory process.
2,3

One of the most commonly used measurements for subclinical atherosclerosis progression is
carotid artery intima-media thickness (CIMT), which is a structural measure of the distance from
the lumen-intima interface to the media-adventitia interface of the arterial wall.
4
While CIMT
provides anatomic information about arterial wall thickness, it does not measure the composition
of the arterial wall, which is modified by the atherosclerotic process. To measure the composition
of the arterial wall, another indicator of atherosclerosis, the gray-scale median of the intima-media
complex (IM-GSM) is used in research studies.
5
IM-GSM was initially developed to measure
arterial plaque composition by evaluating the echogenicity of ultrasonic images of vascular walls.
B-mode ultrasound imaging was used to measure the plaque echogenicity and further computer
image analysis was used to achieve accurate plaque characterization.
6
Echolucent plaques,
reflected by low IM-GSM values, are rich in lipids and prone to rupture, predicting a higher risk for
future stroke. Echogenic plaques on the other hand contain more fibrous tissue and are
2

represented by higher IM-GSM values.
7
Also, there is a significantly moderate and negative
correlation between CIMT and IM-GSM; in a sample of 643 healthy postmenopausal women, the
correlation coefficient is -0.43 (p-value < 0.0001).
8
This suggests that these two non-invasive
imaging indicators reflect different, but nonetheless correlated aspects of atherosclerosis.
Increasing arterial stiffness is a hallmark of aging and may contribute to life-threatening disease
outcomes such as stroke and heart failure.
9
Both structural and cellular elements of the vessel
wall are possibly involved in the development of vascular stiffness. Elastin and collagen are two
structural proteins that contribute to the stability, resilience, and compliance of the vascular wall.
The stability of the vessel wall is maintained by a balanced production and degradation of these
two proteins.
10
Inflammatory processes dysregulate this balance, resulting in excessive abnormal
collagen production and diminished quantities of normal elastin, leading to arterial stiffness.
11

Additionally, increased luminal pressure, also known as hypertension, stimulates the production
of excessive collagen.
12
In addition to structural changes, the stiffness of arteries is also heavily
influenced by cellular change, particularly by endothelial cell signaling and vascular smooth
muscle cell (VSMC) tone.
10

For women in the same age group, postmenopausal women have a CVD risk that is 2.6 times
that of premenopausal women,
13
suggesting that menopause is a risk factor for CVD, including
atherosclerosis. Our primary aim for this paper is to better understand the pathophysiologic
dynamics between measures of subclinical atherosclerosis and arterial stiffness in
postmenopausal women followed for an average of 5 years. We hypothesize that arterial stiffness

3
is associated with arterial thickening and GSM (lipid deposition) in postmenopausal women
population with longitudinal assessments of arterial stiffness, IM-GSM, and CIMT.

4

Methods
Study Design
This is a secondary analysis using data collected from 643 healthy postmenopausal women
participating in the Early versus Late Intervention Trial with Estradiol (ELITE). ELITE was a single-
center, randomized, double-blinded, placebo-controlled clinical trial evaluating the effect of
hormone therapy (HT) on subclinical atherosclerosis progression in postmenopausal women
stratified by time since menopause; early postmenopause (<6 years since menopause) and late
postmenopause (≥10 years since menopause). A total of 643 postmenopausal women were
randomly assigned to either hormone therapy (HT) or to placebo within each stratum of time since
menopause.
The participants did not have regular menses for at least 6 months and their serum estradiol
concentration (E2) was <25 pg/ml. The women did not have any clinically evident cardiovascular
disease (CVD), diabetes, cancer, or any other chronic disease, and did not take HT in the past 6
months.
ELITE was approved by the University of Southern California Institutional Review Board. All
participants provided written informed consent. An External Data Safety Monitoring Board with
expertise in women’s health, menopausal health, hormone replacement therapy, cardiovascular
disease, clinical trials, and biostatistics, supervised the safety of participants and trial conduct.
15

Randomization and Treatment

5
Besides the number of years-since-menopause (<6 years or ≥10 years), other randomization
stratification factors were hysterectomy status (yes, no) and baseline common carotid artery
intima-media thickness (CIMT) (<0.75mm or ≥0.75mm). Participants were randomly and blindly
assigned to either HT or to placebo in a 1:1 ratio within each randomization stratum. Women with
a uterus who were assigned to HT were given oral micronized 17 β-estradiol 1mg/day along with
vaginal micronized progesterone gel 4% 45mg/day for 10 days in a month. Women in the placebo
group with a uterus were given matching oral and gel placebos. Women who had a hysterectomy
were randomly assigned to oral micronized 17 β-estradiol 1mg/day or a matching placebo.
Participants, investigators, staff, imaging specialists, and data monitors were blinded to treatment
group assignment.
15

Participant Follow-up during the Trial
ELITE was initially designed to be a 5-year trial, which included a 3-year recruitment period and
2-5 years of randomized treatment. The trial was extended for an additional 2.5 years in order to
extend participant follow-up and collect additional trial outcomes (a cardiac CT). Following
randomization, participants were evaluated every month for the first 6 months and every 6 months
for the rest of the trial. Fasting blood samples were collected every 6 months to measure
biomarkers of CVD including lipids, carbohydrate metabolites, and others.
15
Important health
measures including blood pressure, body mass index (BMI), smoking, alcohol use, and physical
activity were collected every 6 months. A structured 7-day physical activity recall was summarized
as the total weekly metabolic equivalent of energy expenditure (MET) calculated as weekly hours

6

of moderate and vigorous activity.
14

Common Carotid Artery Ultrasonogram
The primary outcome of the ELITE was subclinical atherosclerosis measured with high-resolution
B-mode ultrasound imaging of the far wall of the right common carotid artery thickness (CIMT)
16

measured at baseline and every 6 months during the trial. The ultrasound procedure is highly
precise and reproducible as the measure is taken over a 1 cm area of the common carotid artery
(CCA), proximal to the bifurcation of the CCA.
22
CIMT is assessed from the visualization of two
echogenic lines in B-mode images that represent the interface between lumen-intima and media-
adventitia.
A second measure of subclinical atherosclerosis derived from the carotid ultrasound images was
the Gray-scale median of the intima-media complex (IM-GSM), which is a measure of lipid
deposition. Low IM-GSM values indicate echolucent areas with more lipid deposition, and high
IM-GSM values indicate echogenic areas with less lipid deposition.
18
Echolucent structures are a
strong predictor of all-cause mortality, including CVD mortality, and atherosclerosis, even in the
absence of other risk factors and thicker CIMT.
19

A third measurement of atherosclerosis, also derived from the carotid artery ultrasound procedure
was arterial stiffness, which included two measures: arterial distensibility, and arterial compliance.
Arterial compliance measures the ability of an arterial wall to distend and increase in volume with
increasing pressure. Arterial compliance is given by:

7
𝐶 =∆𝑉/∆𝑃
Where ∆𝑃 stands for the change in arterial pressure, and ∆𝑉 is the change in arterial volume.
23

Arterial compliance has an inverse relationship with arterial stiffness.
20
Arterial distensibility is a
measurement of change in the arterial volume against cardiac pulsation and relaxation.
21
The
formula is as follows:
𝐷 =∆𝑉/(∆𝑃∙𝑉)
Statistical Analysis
Baseline cross-sectional analysis: Participants' baseline characteristics, such as demographic
characteristics (age, sex, race, body mass index), medical history, CVD risk factors (blood
pressure, smoking status, lipids), and previous HT, were summarized. Continuous variables were
reported as medians with an interquartile range, and categorical variables were reported using
frequency and percentages (Table 1). The correlation between baseline CIMT, IM-GSM, arterial
distensibility, and compliance was determined by Pearson’s correlation (Table 2).
Dependent variables arterial compliance and arterial distensibility are both continuous variables.
The independent variables were also all continuous variables except Race. The goodness-of-fit
shows the sample data fits a rather normal distribution. Therefore, linear regression models were
used to evaluate the cross-sectional associations between CVD risk factors and arterial stiffness
measures (arterial distensibility and arterial compliance) at baseline univariably (Table 3) followed
by multivariable linear regression models including the variables that were associated with the

8

arterial stiffness measures at p<0.05 in univariable analysis (Table 4). Diastolic blood pressure
(DBP) was eliminated from the multivariable model to avoid collinearity with systolic blood
pressure (SBP) (Pearson’s r = 0.70; p-value < 0.0001).
Separate models were evaluated for each stiffness measure (distensibility and compliance) and
traditional cardiovascular variables including DBP, SBP, LDL cholesterol, HDL cholesterol, and
triglyceride levels. Since age, race, and triglyceride levels were significantly associated with both
arterial stiffness measures and those are known to correlate with atherosclerosis, those variables
were added in the multivariate model as covariates to adjust for confounding bias (Table 5, Table
5a, Table 5b).
Longitudinal associations: Mixed effect linear models were used to address the primary
hypothesis evaluating whether baseline subclinical atherosclerosis measures, measured at the
screening visit, predict arterial stiffness progression over a 5-year period. A two-way interaction
term of years since baseline measures and the baseline measures of subclinical atherosclerosis
(exposure) were tested for an association with the longitudinal measures of arterial stiffness
(outcome). Separate models were run for each measure of arterial stiffness: arterial compliance
and distensibility. Participant-level random effects were specified for the intercept (baseline
arterial compliance and distensibility) and the slope indicating the rate of changes per year in
arterial compliance and distensibility. The atherosclerosis measures of CIMT and IM-GSM were
modeled as fixed effects.
Stratified analyses of the primary mixed effects model were performed by baseline lipid-lowering

9
medication intake (yes/no), randomization group (HT/placebo), and postmenopause group
(early/late). The modifying role of the stratifying variables was tested by including a three-way
interaction term (between the independent variable*time in years since baseline visit*the
stratifying variable) as a covariate in the mixed models. All analyses were conducted using SAS,
version 9.4.

10

Results
Baseline Characteristics
Among the 643 participants who participated in the ELITE study, 596 participants underwent at
least one follow-up visit for a carotid ultrasound assessment.
18
297 women were randomized to
receive HT and 299 women were randomized to the placebo group.
Table 1 summarizes the participants’ demographic factors and clinical variables at baseline. The
mean (SD) age was 60.6 (6.9) years at enrollment. The mean (SD) CIMT was 0.88 mm (0.11 mm)
at baseline. The baseline mean (SD) IM-GSM was 59.92 (11.00). Participants were overweight
(average BMI (SD) 27.2 (5.4) kg/m
2
), with systolic blood pressure (average SBP (SD) 117.7 (12.2)
mmHg) and diastolic blood pressure (average DBP (SD) 75.0 (7.0) mmHg) within normal range,
with a borderline high LDL cholesterol (average LDL (SD) 135.9 (31.2) mg/dl) and a normal HDL
cholesterol (average HDL (SD) 66.16 (17.74) levels. The majority of the participants were non-
Hispanic White (69.6%); 13.3% were Hispanic, 8.7% were Black, and the remaining 8.4% were
Asian. For smoking history, 3.2% of the women were current smokers, 37.1% were former
smokers, and 59.7% never smoked.

11
Table 1. Demographic and Clinical Variables (N=596).
Characteristics Mean (SD)
Age, years 60.6 (6.9)
Race (%)
White non-Hispanic 415 (69.6)
Black non-Hispanic 52 (8.7)
Hispanic 79 (13.3)
Asian 50 (8.4)
Smoking History (%)
Current 19 (3.2)
Former 221 (37.1)
Never 356 (59.7)
Current hypertension medications (%) 122 (20.5)
Body mass index, kg/m2 27.2 (5.4)
Systolic blood pressure, mmHg 117.7 (12.2)
Diastolic blood pressure, mmHg 75.0 (7.0)
LDL cholesterol, mg/dl 135.9 (31.2)
HDL cholesterol, mg/dl 66.16 (17.74)
Triglycerides, mg/dl 106.52 (53.6)
Carotid artery intima-media thickness, mm 0.88 (0.11)
IM-GSM (unitless) 59.92 (11.00)

Baseline Correlation Between CIMT, IM-GSM, and Arterial Stiffness Measures
At baseline, CIMT was moderately inversely correlated with IM-GSM (Pearson’s r = -0.43, p <
0.0001). Arterial compliance was strongly positively correlated with arterial distensibility
(Pearson’s r = 0.88, p < 0.0001). IM-GSM had negligible correlation with both arterial compliance
and arterial distensibility (Pearson’s r = 0.056, p = 0.17 for arterial distensibility; Pearson’s r =
0.074, p = 0.07 for arterial compliance). CIMT also had a negligible correlation with arterial
stiffness (Pearson’s r = -0.018, p = 0.65 for arterial distensibility; Pearson’s r = -0.05, p = 0.22 for
arterial compliance; Table 2).

12

Table 2. Correlation Matrix of the Atherosclerosis Measures.
IM-GSM CIMT Arterial
distensibility
Arterial
compliance
IM-GSM -0.43
(<0.0001)
0.06
(0.17)
0.07
(0.07)
CIMT -0.43
(<0.0001)
0.02
(0.65)
-0.05
(0.22)
Artery
distensibility
0.06
(0.17)
-0.02
(0.65)
0.88
(<0.0001)
Artery compliance 0.07
(0.07)
-0.05
0.22
0.88
(<0.0001)

Risk Factors of Arterial Stiffness
Table 3 shows the univariate associations of common cardiovascular risk factors with the two
measures of arterial stiffness, arterial compliance, and distensibility. Black race was inversely and
statistically significantly associated with lower arterial distensibility compared to White participants;
the mean difference in arterial distensibility between Black and White participants was -
2.333(10
−3
× mmHg
−1
) (β-estimate = -2.333; 95% confidence interval [CI], -0.11 to 0.05; p-value
= 0.0018). Black race was also inversely associated with arterial compliance, the difference in
arterial compliance between Black and White race was -0.104μm/mmHg (β-estimate = -0.104;
95% CI, -0.006 to 0.002; p-value = 0.04). Triglyceride level was positively associated with arterial
distensibility; for each mg/dl increase of triglycerides, arterial distensibility increased by
0.015(10
−3
× mmHg
−1
) (β-estimate = 0.015; 95% CI, 0.005 to 0.03; p-value = 0.004). Triglyceride
level was also positively associated with arterial compliance; for each mg/dl increase of
triglycerides, arterial compliance increased by 0.0006μm/mmHg (β-estimate = 0.0006; 95% CI,
0.00003 t0 0.001; p-value = 0.04). Age, Hispanic race, BMI, physical activity, LDL cholesterol,

13
DBP, antihypertensive medication use, and glucose were inversely but not statistically
significantly associated with arterial stiffness (Table 3, all p-values > 0.05). Asian race, LDL
cholesterol, and SBP were positively but not statistically significantly associated with arterial
stiffness (Table 3, all p-values > 0.05).
In multivariable linear regression analysis, Black non-Hispanic race was significantly inversely
associated with arterial distensibility (Table 4, β-estimate = -2.11; 95% CI, -4.1 to 0.12; p-value =
0.04). Triglyceride level was significantly directly associated with arterial distensibility and arterial
compliance (Table 4, β-estimate = 0.02; 95% CI, 0.006 to 0.0039; p-value = 0.002 for arterial
distensibility; β-estimate = 0.0007; 95% CI, 0.00003 to 0.001, p-value = 0.04 for arterial
compliance). Triglyceride level and arterial distensibility have about the same level of strength
direct association in the multivariable model as in the univariate model.
Table 3. Univariable Associations of Cardiovascular Risk Factors with Arterial Stiffness Measures.
Arterial Distensibility(10
−3
×
mmHg
−1
)
Arterial Compliance(μm/mmHg)
Variables β-Estimate
(95%CI)
SE p-
value
β-Estimate (95%Cl) SE p-value
Age, years -0.032 (-0.11-0.05) 0.04 0.42 -0.002 (-0.006-
0.002)
0.002 0.27
Race (%)
White non-Hispanic Reference Reference
Black non-Hispanic -2.333 (-4.27—0.4) 0.984 0.0018 -0.104 (-0.21—
0.003)
0.052 0.04
Hispanic -1.267 (-2.87-0.34) 0.818 0.12 -0.042 (-0.13-0.043) 0.043 0.33
Asian 1.737 (-0.21-3.69) 0.992 0.08 0.096 (-0.006-0.2) 0.052 0.07
Body mass index,
kg/m
2

-0.021 (-0.12-.08) 0.051 0.68 -0.002 (-0.007-
0.003)
0.003 0.46
Physical activity, MET
hours/week
-0.005 (-0.03-0.02) 0.013 0.72 -0.0002 (-0.001-
0.001)
0.0007 0.8

14

LDL cholesterol, mg/dl 0.005 (-0.01-0.02) 0.009 0.56 0.0002 (-0.001-
0.001)
0.0005 0.72
HDL cholesterol, mg/dl -0.012 (-0.04-0.02) 0.015 0.43 -0.0008 (-0.002-
0.0001)
0.0008 0.35
Triglycerides, mg/dl 0.015 (0.005-0.03) 0.005 0.004 0.0006 (0.00003-
0.001)
0.0003 0.04
Systolic blood pressure,
mmHg
0.0002 (-0.04-
0.04)
0.023 0.99 -0.001 (-0.004-
0.001)
0.001 0.26
Diastolic blood
pressure, mmHg
-0.014 (-0.09-0.06) 0.039 0.72 -0.001 (-0.005-
0.003)
0.002 0.58
Antihypertensive
medication use
-0.901 (-2.18-0.37) 0.648 0.17 -0.054 (-0.12-0.012) 0.034 0.11
Glucose, mg/dl -0.009 (-0.06-0.04) 0.027 0.73 -0.001 (-0.004-
0.002)
0.001 0.41

Table 4. Multivariable Associations of Cardiovascular Risk Factors with Arterial Stiffness Measures at baseline.
Arterial Distensibility(10
−3
× mmHg
−1
) Arterial Compliance(μm/mmHg)
Variables β-Estimate SE p-value β-Estimate SE p-value
Black non-
Hispanic
-2.09 (-4.00- -0.18) 0.97 0.03 -0.1 (-0.2-0.002) 0.05 0.05
Triglycerides,
mg/dl
0.014 (0.004-0.02) 0.005 0.007 0.0005 (-0.00001-
0.001)
0.0003 0.06
Note: Only include variables with p-value<0.05 in the univariate model: Black race, and triglycerides in the multivariable model.

Association Between Subclinical Atherosclerosis and Arterial Stiffness Progression
Table 5: The Association of Baseline Subclinical Atherosclerosis Measures with Arterial Stiffness Progression (n = 593).
IM-GSM P Value CIMT P Value
Arterial Distensibility
Mean rate of change (95%
Cl)
-0.004 (-0.02-0.01) 0.61 -0.00006 (-0.0007-0.0006) 0.87
Arterial Compliance
Mean rate of change (95%
Cl)
-0.9 (-2.4-0.53) 0.21 -0.04 (-0.11-0.03) 0.27
After 5 years of follow-up, 3 participants were eliminated because of crucial data missing, the 593
participants in the whole cohort did not show any significant association between two baselines

15
atherosclerosis measures: IM-GSM and CIMT, with arterial stiffness progression rate (all p-
value > 0.20) (Table 5).

Association Between IM-GSM and Arterial Stiffness Progression

When stratified by the randomized treatment group, the baseline IM-GSM was non-significantly
negatively associated with arterial stiffness progression rate for the placebo group (𝛽 (95% CI) -
0.0002μm/mmHg (-0.001, 0.0008) of arterial compliance per year and -0.009(10
−3
× mmHg
−1
) (-
0.03, 0.01) of arterial distensibility per year for the placebo group) (Table 5a). A non-significant
positive association was observed between baseline IM-GSM and arterial stiffness progression
rate for the group that received estradiol (𝛽 (95% CI) 0.00006μm/mmHg (-0.003, 0.002) of arterial
compliance per year and 0.0005(10
−3
× mmHg
−1
) (-0.04, 0.04) of arterial distensibility per year).
The association of baseline IM-GSM with the rate of arterial stiffness progression between the
two treatment groups did not differ (3-way interaction p-value = 0.67 for arterial compliance; 3-
way interaction p-value = 0.46 for arterial distensibility) (Table 5a).

16

For the whole antihyperlipidemic use stratum, a non-significant negative association was
observed between baseline IM-GSM and arterial stiffness progression rate. There was no
significant difference in these associations between antihyperlipidemic use stratum (3-way
interaction p-value = 0.81 for arterial compliance; 3-way interaction p-value = 0.82 for arterial
distensibility) (Table 5a).
The time since menopause stratum showed a non-significant positive association between
baseline IM-GSM and arterial compliance progression rate (𝛽 (95% CI) 0.00002μm/mmHg (-
0.0009, 0.0009), and a non-significant negative association between baseline IM-GSM and
arterial distensibility progression rate (𝛽 (95% CI) -0.0002(10
−3
× mmHg
−1
) (-0.02, 0.02) for
women who were in the early postmenopausal group. A non-significant negative association was
also observed between baseline IM-GSM and arterial stiffness progression rate for the late
postmenopausal group. These associations between early versus late postmenopausal groups
were not statistically significantly different (3-way interaction p-value = 0.85 for arterial compliance;
3-way interaction p-value = 0.64 for arterial distensibility) (Table 5a).

Association Between CIMT and Arterial Stiffness Progression

17

The association between CIMT and arterial stiffness progression after stratifications has similar
results compared to the previous Table 5a IM-GSM model. No significant difference was observed
in the associations between treatment group stratum (3-way interaction p-value = 0.37 for arterial
compliance; 3-way interaction p-value = 0.39 for arterial distensibility). For the antihyperlipidemic
use stratum, there was no significant difference in the association of baseline CIMT with arterial
stiffness progression rate (3-way interaction p-value = 0.07 for arterial compliance; 3-way
interaction p-value = 0.09 for arterial distensibility). There is also no significant difference in the
association between early vs. late postmenopause groups (3-way interaction p-value = 0.26 for
arterial compliance; 3-way interaction p-value = 0.49 for arterial distensibility) (Table 5b).

18

Discussion
The result of this longitudinal study shows that arterial stiffness progression is not related to
subclinical atherosclerosis conditions measured by either CIMT or IM-GSM. Further stratified by
baseline lipid-lowering medication intake, hormone treatment group, and postmenopause group,
there is still no significant association between arterial stiffness progression and baseline CIMT
and IM-GSM. A possible explanation for this non-significant result could be that atherosclerosis
does not lead to arterial stiffness. Many research results suggest that arterial stiffness is just
another predictor of cardiovascular disease. A meta-analysis of 17 studies that used pulse wave
velocity (PWV) as an arterial stiffness indicator, showed an increase of PWV by 1 m/s
corresponded to a 14% increased risk of atherosclerosis. Subjects with a higher baseline CV risk
(renal disease, and hypertension) tend to have a higher predictive ability.
29
Of note, our study
population was overall healthy postmenopausal women without any clinically evident CVD or any
chronic disease, which might explain the null association between atherosclerosis and arterial
stiffness. This explanation is also supported by literature showing arterial stiffness and
atherosclerosis are a consequence of vascular calcification, that is driven by the vascular smooth
muscle cells (VSMCs).
30
Both the intimal and medial layers of arteries could have vascular
calcification with different clinical complications. Arterial medial calcification (AMC) could be
caused by the loss of inhibitors of calcification, aging, cell death or damage,
30
which is linked to
arterial stiffness. Compared with AMC, patients with arterial intimal calcification (AIC) often show
lipid accumulation and inflammation cell infiltration.
30
AIC has a strong correlation with

19
atherosclerotic plaque burden,
31
which can predict adverse arterial events including
atherosclerosis.
32
Although AMC and AIC have different pathways to drive VSMC change, it would
lead to arterial calcification.
At baseline, our data show a statistically significant moderate correlation between CIMT and IM-
GSM (Pearson’s r = -0.43). Prior studies report a similar inverse correlation from -0.17 to -0.51.
19,
24, 25, 26
This inverse correlation does reflect the fact that CIMT and IM-GSM measure different
aspects of the arterial wall due to atherosclerosis. We also see a statistically significant strong
positive correlation between baseline arterial distensibility and arterial compliance (Pearson’s r =
0.88). This result accords with the fact that these two measurements capture the same aspect of
arterial stiffness.
Univariately, common cardiovascular risk factors (Black race and triglycerides) were correlated to
both arterial compliance and arterial distensibility. This finding does not really make much sense.
Some studies used the measurement of pulse wave velocity (PWV) to reflect arterial stiffness
because this measurement is non-invasive and cost-effective.
27
However, the significant level of
association between continuous TGs and arterial stiffness, measured by arterial distensibility and
arterial compliance in our study, is not that strong. So, TGs could be used as a supplementary
predictor for arterial stiffness. Black race tends to have lower socioeconomic status, have health
problems such as obesity, and perceived racism, all of which have a significant impact on arterial
stiffness.
28

In conclusion, our data do not indicate any association between arterial stiffness and subclinical

20

atherosclerosis. We did not find any cross-sectional or longitudinal association between arterial
stiffness and subclinical atherosclerosis. A rather reasonable explanation for this result is that
vascular calcification is the cause of arterial stiffness and atherosclerosis. However, our study
population was selectively healthy without any clinical evidence of CVD. A better understanding
of etiology and pathogenesis could help scientists focus on the right future directions for
atherosclerosis and arterial stiffness research.

21
References

1. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-874.
2. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001;104:503-516.
3. Falk E. Pathogenesis of atherosclerosis. Journal of the American College of
Cardiology.2006;47(8):C7-C12.
4. Polak JF, Pencina MJ, Pencina KM, et al. Carotid-wall intima-media thickness and
cardiovascular events. N Engl J Med. 2011;365:213-221.
5. Gronholdt MI, Nordestgaard BG, Schroeder TV, et al. Ultrasonic echolucent carotid plaques
predict future strokes. Circulation 2001;104:68-73.
6. El-Barghouty N, Geroulakos G, Nichlaides A, et al. Computer-assisted carotid plaque
characterization. Eur J Vac Endovasc Surg. 1995;9:389-393.
7. Goncalves I, Lindholm MW, Pedro LM, et al. Elastin and calcium rather than collagen or lipid
content are associated with echogenicity of human carotid plaques. Stroke. 2004;35(12);2795-
2800.
8. Karim R, Xu W, Kono N, et al. Comparison of cardiovascular disease risk factors between 2
subclinical atherosclerosis measures in healthy postmenopausal women: carotid artery wall
thickness and echogenicity. Journal of Ultrasound in Medicine. 2022;9999:1-10.
9. Lakatta EG, Levy D. Arterial and cardiac aging: major thresholders in cardiovascular disease
enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139-146.
10. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial
stiffness. Arteriosler Thromb Vasc Biol. 2005;25:932-943.

22

11. Johnson CP, Baugh R, Wilson CA, et al. Age related changes in the tunica media of the
vertebral artery: implications for the assessment of vessels injured by trauma. J Clin Pathol.
2001;54:139-145.
12. Xu C, Zarins CK, Pannaraj PS, et al. Hypercholesterolemia superimposed by experimental
hypertension induces differential distribution of collagen and elastin. Arterioscler Thromb Vasc
Biol. 2000;20:2566-2572.
13. Kannel WB, Hjortland M, Mcnamara PM, et al. Menopause and risk of cardiovascular disease:
the Framingham study. Annals of Internal Medicine. 1976;85(4):447-452.
14. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late
postmenopausal treatment with estradiol, N. Engl. J. Med. 2016;374:1221-1231.
15. Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardiovascular data from the
early versus late intervention trial with estradiol testing the menopausal hormone timing
hypothesis. Menopause. 2015;22:391-401.
16. Willeit P, Tschiderer L, Allara E, et al. Carotid intima-media thickness progression as
surrogate marker for cardiovascular risk: meta-analysis of 119 clinical trials involving 100 667
patients. Circulation. 2020;142:621-642.
17. Pignoli P, Tremoli E, Poli A, et al. Intimal plus medial thickness of the arterial wall: a direct
measurement with ultrasound imaging. Circulation. 1986;74:1399-1406.
18. Karim R, XU W, Kono N, et al. Effect of menopausal hormone therapy on arterial wall
ecomorphology: Results from the early versus late intervention trial with estradiol (ELITE).
Maturitas. 2022:162;15-22.
19. Wohlin M, Sundstrom J, Andren B, et al. An echolucent carotid artery intima-media complex
is a new and independent predictor of mortality in an elderly male cohort, Atherosclerosis.
2009;205:486-491.
20. Papaioannou TG, Protogerou AD, Stergiopulos N, et al. Total arterial compliance estimated
by a novel method and all-cause mortality in the elderly: the PROTEGER study. Age.
2014;36:1555-1563.

23
21. Godia EC, Madhok R, Pittman J, et al. Carotid artery distensibility: a reliable study, J.
Ultrasound Med. 2007;26:1157-1165.
22. Jashari F, Ibrahimi P, Johansson E, et al. Carotid IM-GSM is better than IMT for identifying
patients with multiple arterial disease. Scandinavian Cardiovascular Journal. 2018;52(2):93-99.
23. Shirwany NA; Zou M. Arterial stiffness: a brief review. Acta Pharmacologica Sinica.
2010;31:1267-1276
24. Jung M, Parrinello CM, Xue XM, et al. Echolucency of the carotid artery intima-media complex
and intima-media thickness have different cardiovascular risk factors relationships: the Women’s
Interagency HIV Study. J Am Heart Assoc. 2015;4:e001405.
25. Peters SA, Lind L, Palmer MK, et al. Increased age, high blood mass index and low HDL-C
levels are related to an echolucent carotid intima-media: the METEOR study. J Intern Med.
2012;272:257-266.
26. Andersson J, Sundstrom J, Gustavsson T, et al. Echogenicity of the carotid intima-media
complex is related to cardiovascular risk factors, dyslipidemia, oxidative stress and inflammation:
the prospective investigation of the vasculature in Uppsala seniors (PIVUS) study. Atherosclerosis.
2009;204:612-618.
27. Wang X, Ye P , Cao R, et al. Triglycerides are a predictive factor for arterial stiffness: a
community-based 4.8-year prospective study. Lipids in Health and Disease. 2016;15:97
28. Schutte AE, Kruger R, Gafane-Matemane LF, et al. Ethnicity and arterial stiffness.
Arteriosclerosis, Thrombosis, and Vascular Biology. 2020; 40:1044-1054.
29. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-
cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol.
2010;55(13):1318-1327.
30. Durham AL, Speer MY, Scatena M, et al. Role of smooth muscle cells in vascular calcification:
implications in atherosclerosis and arterial stiffness. Cardiovascular Research. 2018;114:590-600.

24

31. Sangiorgi G, Rumberger JA, Severson A, et al. 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.
32. Taylor AJ, Burke AP , O’Malley PG, et al. A comparison of the Framingham risk index, coronary
artery calcification, and culprit plaque morphology in sudden cardiac death. Circulation.
2000;101:1243-1248.

Abstract (if available)

Abstract Objectives: To evaluate if atherosclerosis causes arterial stiffness progression.

Background: Atherosclerosis can be assessed by ultrasound measurement of carotid intima-media thickness and gray-scale median of the intima-media complex. An association between arterial stiffness and atherosclerosis was also observed in many studies. We hypothesize that atherosclerosis is a precursor of arterial stiffness.

Methods: 643 healthy postmenopausal women were included in the analyses. Carotid intima-media thickness, gray-scale median of the intima-media complex, and arterial stiffness were measured by either B- or M-mode ultrasonogram. Mixed effects models include baseline measures of carotid intima-media thickness and gray-scale median of the intima-media complex as exposure variables and longitudinal measures of arterial compliance and arterial distensibility as outcome variables. Further analyses were stratified by lipid-lowing medication use, randomization group, and postmenopausal group.

Results: Overall, there is no significant association between atherosclerosis and arterial stiffness progression because the p-values’ are all bigger than 0.05. We also do not see any significant association between the three stratification groups.

Conclusions: The study result fails to conclude our hypothesis that arterial stiffness is caused by atherosclerosis.

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Asset Metadata

Creator Jin, Ziyu (author)

Core Title Association of arterial stiffness progression with subclinical atherosclerosis measurements in postmenopausal women

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Degree Conferral Date 2023-12

Publication Date 09/12/2023

Defense Date 09/12/2023

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

Tag arterial stiffness,atherosclerosis,hormone treatment,OAI-PMH Harvest,poastmenopausal women

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Karim, Roksana (committee chair), Hodis, Howard (committee member), Mack, Wendy (committee member)

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