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University of Southern California Dissertations and Theses
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Artery wall injury and LDL-cholesterol in early atherosclerosis: The Los Angeles atherosclerosis study
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Artery wall injury and LDL-cholesterol in early atherosclerosis: The Los Angeles atherosclerosis study
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ARTERY WALL INJURY AND LDL-CHOLESTEROL
IN EARLY ATHEROSCLEROSIS
THE LOS ANGELES ATHEROSCLEROSIS STUDY
By
Ping Sun
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(Preventive Medicine / Public Health)
May, 1999
Copyright 1999 Ping
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UMI Number: 9933790
UMI Microform 9933790
Copyright 1999, by UMI Company. All rights reserved.
This microform edition is protected against unauthorized
copying under Title 17, United States Code.
UMI
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UNIVERSITY OF SOUTHERN CALIFORNIA
THE GRADUATE SCHOOL
UNIVERSITY PARK
LOS ANGELES. CALIFORNIA 90007
This dissertation, written by
PING SUA/
v
under the direction of hJ.A.... Dissertation
Committee, and. approved by all its members,
has been presented to and accepted by The
Graduate School, in partial fulfillment of re
quirements for the degree of
DOCTOR OF PHILOSOPHY
Peart o f Graduate Studies
DISSERTATION COMMITTEE
Chairperson
'jwd
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My Motherland: The People’s Republic of China
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ACKNOWLEDGMENTS
I would like to acknowledge James Dwyer, Ph.D., Kathleen Dwyer,
Ph.D., C. Noel Bairey Merz, M.D., Wei Sun, MS., Lisa Nicholson, MS., Cheryl
Nordstrom, MPH, Lora Whitfield, R.N., and various other colleagues with
whom I have participated in the Los Angeles Atherosclerosis Study. I
appreciate the opportunity to have been part of this well designed and
wonderfully executed longitudinal study of atherosclerosis.
I thank my committee members for their individual contributions to this
research report: James Dwyer, Ph.D.; Andy Johnson, Ph.D.; Stanley Azen,
Ph.D.; Wendy Mack, Ph.D.; Gordon Liu, Ph.D.; and C. Noel Bairey Merz, M.D.
I am especially grateful for the encouragement and support given by
my wife, Min Xiang, and my daughter, Brianna Sun. It was Brianna’s first
perceivable movement in Min’s tummy, and Brianna’s beautiful first smile in
my hands that rang the bell for me to dash to the finish line of my 10+ years of
graduate studies. I would like to thank my parents: Pengqing Sun and
Xiuyuan Guo, my brother and sister in law: Wei Sun and Lora Liu, my sister
and brother in law: Li Sun and Jianwen Zhu, my nieces Angel and Peipei, my
nephew Andrew, and my other family members, for their being my permanent
source of energy.
iii
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TABLE OF CONTENTS
LIST OF TABLES V
LIST OF FIGURES VI
LIST OF ABBREVIATIONS VIII
Abstract IX
1 Introduction 1
1.1 Significance 1
1.2 Ultrasonographically Measured CCA IMT and Cardiovascular Disease 2
1.3 Risk Factors for Thickened IMT and IMT Progression 4
2 Methods 10
2.1 The Los Angeles Atherosclerosis Study 10
2.2 Measures 13
2.3 Statistical Models 17
3 Results 20
3.1 The Interaction of LDL and SBP with IMT and AIMT 20
3.2 Short Term Change in SBP.DBP, and HR and IMT 32
3.3 The Interaction of LDL and Cigarette Smoking with IMT and AIMT 43
4 Conclusions 56
References 71
iv
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LIST OF TABLES
TABLE
1 Analysis of Interactive Effects 19
2 Summary of Related Variables by Sex And SBP Tertile Groups 21
3 Cross-sectional Linear Relationship between IMT and LDL 24
Cholesterol, by SBP Tertile Group
4 Summary of Study Variables in 414 Subjects in Longitudinal 27
analyses, by SBP Tertile Groups
5 Longitudinal Linear Relationship between 18 Months AIMT and 31
LDL Cholesterol, by SBP Tertile Group
6 Summary of Changes in SBP, DBP, and Heart Rate during 32
Ultrasound Examination
7 Linear Effects of Change in SBP, DBP, and Heart Rate during 34
Ultrasound Examination on IMT (mm).
8 Summary of Study Variables, by Tertile Group of Change in 38
SBP during ultrasound examination
9 Pearson Correlation between Change in SBP, DBP, and Heart 41
Rate during Ultrasound Examination and Other Study
Variables, by Sex
10 Summary of Relevant Studying Variables, by Sex and 44
Smoking Status
11 Linear Cross-sectional Relationship between IMT and LDL 48
Cholesterol, by Smoking Status
12 Linear Longitudinal Relationship between 18 Month AIMT and 49
LDL Cholesterol, by Smoking Status
V
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LIST OF FIGURES
FIGURE
1 Ultrasound Detection of Arterious Structure Parameter 2
2 Generation of Dysfunctional Endothelium 6
3 Longitudinal Cohort Follow-up Design: The Los Angeles 1 1
Atherosclerosis Study
4 Summary of Subjects in Exam I: The Los Angeles 12
Atherosclerosis Study
5 Longitudinal Ultrasound Probe Positioning and Its Resultant 14
Carotid Artery Image
6 Carotid Artery IMT with LDL-CHOL, by SBP, All Subjects 22
7 18 Month Carotid Artery IMT Progression with LDL-CHOL, By 29
SBP
8 Carotid Artery IMT with ASBP during Ultrasound Examination 35
9 Carotid Artery IMT with ADBP during Ultrasound Examination 36
10 Carotid Artery IMT with AHR during Ultrasound Examination 37
11 Carotid Artery IMT with LDL-CHOL, by ASBP, All Subjects 42
(Sample CA)
12 Carotid Artery IMT with Smoking Status, By Sex 45
13 Carotid Artery IMT with Cumulative Smoking, By Sex 46
14 Carotid Artery IMT with LDL-C, by Smoking Status, Women Only 52
15 Carotid Artery IMT with LDL-C, by Smoking Status, Men Only 53
16 18 Month AIMT with LDL-C, by Smoking Status, Women Only 54
vi
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LIST OF FIGURES
FIGURE
17 18 Month AIMT with LDL-C, by Smoking Status, Men Only
18 Prevalence of Lesion, By Sex
19 Artery Wall Injury, LDL-C, and Early Atherosclerosis, A
Postulated Pathway
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LIST OF ABBREVIATIONS
CCA Common Carotid Artery
CHD Coronary Heart Disease
CHOL Serum Total Cholesterol
CVD Cardiovascular Disease
DBP Seated Diastolic Blood Pressure
ADBP Change in Average Supine and Seated DBP during Ultrasound
Examination
AHR Change in Heart Rate during Ultrasound Examination
AMAP Change in Average Supine and Seated MAP during Ultrasound
Examination
APP Change in Average Supine and Seated PP during Ultrasound
Examination
ASBP Change in Average Supine and Seated SBP during Ultrasound
Examination
HDL High Density Lipoprotein
HR Heart Rate
IMT Intima-Media-Thickness
LDL Low Density Lipoprotein
SBP Seated Systolic Blood Pressure
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ABSTRACT
Background. Hypertension, cigarette smoking, and elevated LDL-C level are
established risk factors for atherosclerosis. Exaggerated cardiac reactivity,
defined as a change in heart rate and/or blood pressure in response to a
stimulus, is a potential risk factor for atherosclerosis. Previous studies have
established the validity of ultrasound detected common carotid artery intima-
media thickness (IMT) as a measure of early atherosclerosis. IMT has been
shown to be positively related with LDL-C, cigarette smoking, and probably
related to change in BP/HR in response to a stimulus. However, there was no
report relate IMT with change in BP/HR during routinely available measures;
there was also no such study that has tried to explore the atherogenic
mechanism of LDL-C, cigarette smoking, SBP, and change in SBP. The
purposes of this dissertation are: 1) to report the relationship between IMT
and cardiavascular activity recovery measured as a fall in blood pressures and
heart rate during a rest period; 2) to test the hypothesis that elevated SBP,
exaggerated change in SBP during a resting period, and current cigarette
smoking may increase the susceptibility of the artery wall to LDL-induced
atherogenesis.
Methods. The ‘Los Angeles Atherosclerosis Study’ is a longitudinal study
following a cohort of 573 utility employees who were aged 40-60 years and
ix
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free of symptomatic cardiovascular disease at recruitment. Data from both the
baseline survey (Exam 1) and a follow-up survey (Exam 3) conducted 18
months later were available for this analysis. Average IMT was assessed
ultrasonographically over a 1 cm segment of CCA 0.25 cm proximal to the
bulb of the carotid bifircation. LDL cholesterol levels were determined from
fasting serum samples, average SBP levels were determined as seated SBP
averaged over before and after ultrasound examination readings,
ASBP/ADBP/AHR during a resting period were measured as changes in
average seated and supine SBP/DBP, and HR during a 15-30 minute supine
period ultrasound scan of the common carotid arteries. Smoking status were
assessed with questionnaire. The linear relationships between IMT and
ASBP/ADBP/AHR were assessed. The linear relationships between IMT/AIMT
and serum LDL-C were assessed in each tertile group of SBP and ASBP (IMT
only), or each smoking status (current, former, and never), within women,
men, both sexes, and with/without excluding diabetes and users of anti-
hypertension and anti-hypercholesterolemia drugs. Covariates adjusted for in
all of the analyses were age, body height, ethnic group (Non-Hispanic White,
Hispanic, African American, Asian, Other), body mass index, and for certain
samples, sex, or diabetes (NIDDM or IDDM/other), and use of medication for
hypertension (yes/no) and hypercholesterolemia (yes/no).
x
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Results. Average IMT at baseline was 0.650 mm in women and 0.673 mm in
men. Average 18 months IMT progression (AIMT) was 0.015 mm in women
and 0.007 mm in men. Interactions between SBP and LDL-C on IMT or AIMT
exist in both women and men. The analyses on all subjects showed that 1)
IMT was significantly related to LDL-C in the high SBP group (p=0.028±0.008
mm/mmol/L, p= 0.0006), but not in the middle (p=-0.005±0.008 mm/mmol/L,
p=0.51) or low (P=-0.003±0.009 mm/mmol/L, p=0.78) SBP groups. The slope
in the high SBP group was significantly greater than in the middle (p=0.004) or
low (p=0.011) SBP groups. 2) AIMT was significantly related to LDL-C in the
high SBP group (p=0.012±0.005 mm/mmol/L, p= 0.012), but not in the middle
(P=-0.006±0.005 mm/mmol/L, p=0.19) or low (P=-0.005+0.005 mm/mmol/L,
p=0.34) SBP groups. The slope in the high SBP group was significantly
greater than in the middle (p=0.006) or low (p=0.01) SBP groups.
IMT was positively related to ADBP during ultrasound examination in
both women (P=0.0038±0.0012 mm/mmHg, p=0.0014) and men
(P=0.0027±0.0015 mm/mmHg, p=0.07). IMT was positively related to AMAP
in both women (p=0.0036±0.0013 mm/mmHg, p=0.007) and men
(P=0.0036±0.0016 mm/mmHg, p=0.026). IMT was not related to ASBP and
APP in either women or men. IMT was positively related to AHR in women
(P=0.0021 ±0.0009 mm/beat/min, p=0.014), but not in men. In men, the
xi
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dependency of IMT on LDL was found to be different across tertile groups of
ASBP (p=0.02 high vs middle, p=0.05 high vs low). Those men whose SBP
dropped the most (-25, -5 mmHg) during the ultrasound examination had a
significantly positive dependency of IMT on LDL (P=0.037±0.012 mm/mmol/L,
p=0.002), while there were no significant relationship between IMT and LDL in
the other two tertile groups of ASBP (p=-0.001±0.011 mm/mmol/L, p=0.95 for
the middle ASBP (-4.5, -0.5 mmHg) group, (p=0.004±0.012 mm/mmol/L,
p=0.77 for the low ASBP (0.0, 10 mmHg) group).
Interactions between smoking and LDL-C on IMT or AIMT were
observed in women, but not in men. In women, IMT was positively related to
LDL-C in current smokers (p=0.029±0.013 mm/mmol/L, p=0.024), but not in
former smokers (p=-0.022±0.012 mm/mmol/L, p=0.08), or those who never
smoked (P=-0.008±0.007 mm/mmol/L, p=0.25); the difference of linear
dependency of IMT on LDL between smoking status was significant (p=0.005
current vs. former, p=0.01 current vs. never). The 18 month AIMT was also
positively related to LDL-C only in current smoking women (p=0.015+0.007
mm/mmol/L, p=0.03), but not in former smoking women (p=-0.003±0.007
mm/mmol/L, p=0.66), or those women who never smoked (p=-0.006±0.004
mm/mmol/L, p=0.17); the between smoking status difference of linear
xii
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dependency of AIMT on LDL was significant (p=0.07 current vs. former,
p=0.01 current vs. never).
Conclusion. These data indicate that elevated SBP level, exaggerated
change in SBP during a resting period, and current cigarette smoking might
accelerate LDL-C induced atherogenesis. These data also indicate that
change in DBP/MAP/HR during a cardiovascular recovering resting period
might be an independent risk factor of early atherosclerosis.
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1 Introduction
1.1 Significance
Atherosclerosis and its sequelae, cardiovascular disease (CVD),
account for more mortality than any other disease in the United States.(1)
Approximately 60% of coronary heart disease (CHD) mortality occurs before
treatment can be administered, and sudden death is the first symptom of CHD
in about 25% of cases. Therefore, to achieve the national goal of reducing
CHD mortality and morbidity, it is crucial to reduce detrimental risk factors to
promote protection and to be able to detect atherosclerosis before its first
symptomatic manifestation. Carotid artery intima-media-thickness (IMT) and
its thickening rate is believed to be one of the earliest asymptomatic changes
in the etiology of atherosclerosis.(2) B-mode ultrasonographic measurement
of common carotid artery IMT, since its first application in 1986,(3) has been
widely employed in epidemiological studies and clinical trials. It has been
proven to be an effective and efficient tool to detect early atherosclerosis to
investigate certain risk factors for atherosclerosis, and to test hypotheses of
atherogenesis.
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1.2 Ultrasonographically Measured CCA IMT and Cardiovascular
Disease
Intima-media-thickness is positively related to age.(4-9) By comparing
autopsy data from patients in Guatemala and Oslo, Norway, the International
Atherosclerosis Project revealed that intimal-medial thickening is both an
Figure 1: Ultrasound Detection of Arterious Structural Parameters
interadventitial diameter
far
wall
IMT
adventitia
media—
intima.
endothelium
aging process and a pathological process.(10) The lesions in the carotid
arteries, cerebral arteries, and coronary arteries are generally known to be
correlated when measured by angiography,(11-14) B-mode
2
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ultrasonography,(15, 16) and autopsy studies.(17-20) As shown in Figure 1,
reflective ultrasound detection of IMT is based on the difference of acoustic
impedance (tissue density * propagation speed of acoustic waves in the
tissue) across the blood-endothelium and media-adventitia boundaries. Since
B-mode ultrasound measurement of carotid artery IMT was first reported in
1986,(3) ultrasonographically measured IMT has been found to be an early
indicator of the risk for coronary heart disease events in prospective
studies.(21-25) Regression of IMT has been found in lipid lowering
intervention trials.(26-30) Thick IMT has also been identified as an
independent risk factor for carotid atherosclerosis in other arteries in cross-
sectional studies.(13, 31-34) Furthermore, conventional CVD risk factors such
as age, cigarette smoking, hypertension, and elevated plasma LDL
cholesterol, have been shown to be risk factors for thicker IMT,(35-37) and
faster IMT progression.(38-40)
B-mode ultrasound measured carotid artery IMT, as a non-invasive
indicator of atherosclerosis and risk for coronary heart disease, is an
inexpensive alternative to MRI and autopsy to obtain highly reliable and
reproducible measures of asymptomatic early atherosclerosis. Although
physical laws determine that the generally employed ultrasound examination
equipped with 5-10 MHz probe offers an axial resolution between 0.1 and 0.2
mm, with measurement averaged over multiple points over a segment of
3
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artery, the precision of IMT measurement can be under 0.1mm.(41-44) The
detectable difference of IMT is further reduced in human population studies.
For example, in the Los Angeles Atherosclerosis Study, it was calculated that
the measures would be adequate to detect a linear metric effect of 0.0025
mm/mmHg between IMT and change in DBP during ultrasound examination,
with a(2)=0.05 and P(1)=0.2.
1.3 Risk Factors for Thickened IMT and IMT Progression
IMT and atherosclerosis/CHD relate to the same generally accepted
factors: age, gender, LDL-C, HDL-C, blood pressure, cigarette smoking, and
body fat patterning. IMT also relates to some factors that have not previous
been related to atherosclerosis. For example, IMT is independently and
positively related to body height, and IMT might be thicker in blacks than
whites.(37)
Although SBP, LDL, and cigarette smoking have been determined to
be risk factors for heart disease and carotid artery IMT, their roles in early
atherosclerosis have not been fully elucidated. The most popular theory of
atherogenesis is the “response-to-injury” hypothesis,(45, 46) which postulates
that various factors, including hemodynamic forces and chemical agents,
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induce dysfunctional alterations in the overlying endothelium.(shown in Figure
2) This injury may then be followed by the aggregation of platelets, oxidized
lipids, and smooth muscle cells in the intimal layer and the eventual formation
of plaques.
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Figure 2: Generation of a Dysfunctional Endothelium
Viral Infection
Thrombin
Oxidized Lipids/
Free Radicals
Activation
Homocysteine
Shear Stress
Hypoxia / Cytokine
H a
1 1 1
1
Altered Permeability
Leukocyte Adhesion
Vasoactive Substances
Response
Procoagulant Activity
Growth Factor/
Chemoattractants
From: DiCorleto, P. and A. Soyombo (1993). "The role of endothelium in atherogenesis." Curr
Opin Lipidol 4: 364-372.
O)
This model of atherogenesis predicts that the atherosclerotic deposition
of LDL may require previous damage to the endothelium by a factor such as
hypertension, or cigarette smoking. Testing of this hypothesis has focused
mainly on experimental data and animal models. Epidemiological studies with
incident heart disease or mortality as end points has contributed to the
identification of risk factors, however, they have offered limited information to
define the etiology of atherosclerosis, particularly in the early stages. The Los
Angeles Atherosclerosis Study provided an opportunity to test the possible
interaction between SBP and cigarette smoking (hypothesized initial agents of
endothelial damage), and LDL in early carotid atherogenesis.
Chronic high blood pressure has been determined to be a risk factor for
CVD(47, 48) and asymptomatic atherosclerosis.(23, 37, 49) Cardiovascular
reactivity, defined as the short term change in heart rate and/or blood
pressure in response to a stimulus, is hypothesized to be a risk factor of
cardiovascular disease. Elevated reactivity has been associated with
increased risk of cardiovascular disease (CVD).(50-52) Diurnal blood
pressure differences (day-night time BP change) are related to CVD(53).
Exaggerated reactivity to mental stress was associated with exercise-
induced(54) and mental stress-induced(55) myocardial ischemia. Other work
has demonstrated that diurnal blood pressure differences were related to
carotid IMT(56). An abnormal nocturnal decrease in blood pressure was
7
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shown to be related to the presence of carotid artery plaque or thicker carotid
artery IMT, although this relationship was not independent of age.(57)
Exaggerated reactivity to mental stress was reported to be associated with
carotid IMT.(58, 59)
Although previous work has demonstrated a positive correlation
between elevated CV reactivity and increased risk for CVD events and
thickened carotid IMT, the mechanisms behind this relationship are unclear.
Moreover, previous reports have not tested the relationship between IMT and
cardiac reactivity during routinely available measures, such as blood pressure
recovery during rest. Accordingly, this study reports the relationship between
IMT and cardiovascular reactivity recovery measured as a fall in BP and HR
during ultrasound examination - presumably a rest period. The hypothesis is
also explored that an exaggerated change in systolic blood pressure may
increase the susceptibility of the artery wall to LDL-induced atherogenesis.
Cigarette smoking is established to be a major risk factor for coronary
heart disease.(60-62) It is also related to the initiation and development of
early atherosclerosis in autopsy studies,(63-65) angiographic studies,(66, 67)
and noninvasive ultrasound studies.(68-72) However, the pathogenic
mechanisms linking smoking to early atherosclerosis have been obscure. The
‘Response-to-lnjury’ hypothesis, which was largely based on basic science
and experimental studies, animal models, and post-mortem autopsy studies,
8
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summarizes the initial stages as injury to endothelial cells and other
subsequent events, such as platelet aggregation, macrophage migration, and
foam cell accumulation.(73) Smoking has been hypothesized to be involved
in all of these initial stages of atherosclerosis.(74) Cigarette smoking,(75-77)
in particular, carbon monoxide(75, 78) and nicotine(79) exposure, appears to
cause biological and morphological changes to endothelium.(80) Cigarette
smoking induced increased levels of catecholamines.(81, 82) such as a-
adrenergic and (5-adrenergic stimulation, which may disrupt endothelial
integrity.(83, 84) Finally, smoking causes elevated plasma LDL cholesterol
levels,(85) increased susceptibility of LDL oxidation,(86, 87) and decreased
levels of HDL,(85) which would facilitate the LDL deposition into the arterial
wall when there was injury in the wall.
During the pathogenic process of early atherosclerosis, both
hypertension and cigarette smoking are hypothesized to be major contributors
in the initial injury of the vessel waii and subsequent cofactors of LDL
deposition. The hypotheses for this study are: 1) IMT and 18 month AIMT are
positively related with LDL only when SBP is high, that is, elevated SBP
operates as a cofactor with LDL in early atherosclerosis. 2) Adjusted for SBP
and other covariates, LDL is related to IMT/AIMT only in current smokers, but
not in former smokers or those who never smoked. 3) IMT is related to short
term change of SBP, DBP, and heart rate in both women and men.
9
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2 Methods
2.1 The Los Angeles Atherosclerosis Study
The Los Angeles Atherosclerosis Study is a prospective cohort follow-
up study, providing ultrasound detected IMT, as well as behavioral and
biological measures in healthy women and men with no history of
cardiovascular disease. In the study, five exams were designed to follow a
total of 573 subject for 36 months, as shown in Figure 3. Age at Exam 1
ranged from 41-62 years in men and 44-61 years in women. Participants
were randomly sampled from employees of a large utility company, with over-
sampling of Hispanics and smokers and a participation rate of 82%. All
participants signed a consent form approved by the Institutional Review Board
of the University of Southern California School of Medicine. The number of
subjects in men and women at baseline and information about medication use
against hypertension or hypercholesterolemia are shown in Figure 4. Data for
the analysis in this dissertation were from Exam 1 (Baseline Exam) and Exam
3 which was designed to be 18 months after the Baseline Exam (actual mean
duration =568 days).
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Figure 3: Longitudinal Cohort Follow-up Study Design: The Los Angeles
Atherosclerosis Study
573*
9 18 27 36
Five Exams in a Period of 36 Months
*: number of subjects in the exam
a: In progress
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Figure 4: Summary of Subjects in Exam I
Atherosclerosis Study
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2.2 Measures
Measures included ultrasound examination of the left and right carotid
arteries in two body positions (supine and lateral in Exam 1, supine only in
Exam 3); a questionnaire concerning demographic information, medication
use, and health behaviors; venipuncture; blood pressure, body height and
weight; and three 24-hour recalls of dietary intake. All measures (except two
of the three 24-hour dietary recalls) were collected in a single examination
conducted in a specially equipped van which was driven to the worksites.
As depicted in Figure 5, Carotid B-mode images were obtained with a
portable B-mode ultrasound scanner (ATL Ultramark 4+) equipped with a 7.5
MHz linear array transducer. Intima-media thickness (IMT) was calculated off
line with a computerized pattern recognition a!gorithm.(43) These procedures
and the reproducibility of the measurements have been reported
e!sewhere.(44) Briefly, IMT is averaged over a 1 cm segment of the common
carotid artery. At Exam 1, IMT was determined for two frames in each of two
body positions (lateral and supine) in the left and right arteries. At Exam 3,
IMT was determined for two frames in supine body positions in the left and
right arteries. The overall IMT measure was the mean of 8 frames. Using this
protocol, the standard deviation of differences between repeated measures of
IMT by different sonographers was 0.029 mm.(44)
13
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Figure 5 : Longitudinal U ltrasound Probe P ositioning and Its Resultant C arotid
A rtery Im age
lo n g itu d in a l
p ro b e
p o s itio n
Smoking information was assessed with a questionnaire. The subjects
were asked whether they were a current or former smoker, or never smoked.
If they were current or former smokers, they would have to answer how many
years they have regularly smoked, and how many cigarettes they smoked
each day during the smoking period. Cumulative pack-year (pack/day * year)
smoking could then be calculated from the answers.
Seated and supine blood pressures were both measured before and
after the ultrasound examination in the brachial artery with a standard mercury
sphygmomanometer. In Exam 1, seated blood pressures were not measured
for 10 out of the total of 576 subjects, these 10 missing seated SBP and DBP
values were imputed from their correspondent supine readings. Average
blood pressures were based on seated measures. Change in SBP and DBP
at each exam is calculated as the average change in supine and seated blood
pressures from the readings before the ultrasound examination and the
readings after the ultrasound examination (after ultrasound examination
reading minus before ultrasound examination reading).
Serum lipid levels in both Exam 1 and Exam 3 were determined from
fasting serum samples. Fasting was defined as a self-reported interval of
more than six hours since the last intake of food. Blood was processed
immediately and stored at -20° C for several days; samples were then stored
at -70° C until analysis. Serum lipids were determined by automated clinical
15
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chemistry analyzers. Serum LDL cholesterol was estimated from total
cholesterol, HDL cholesterol and triglycerides using the formula of Delong et
al,(88, 89) LDL cholesterol was not determined in subjects with fasting serum
triglyceride levels > 300 mg/dL (n=76).
Due to non-standard measurement and error compounding, the
reproducibilities were not good for measures of change in SBP, DBP, and HR
during ultrasound examination. To better assess the average levels of IMT,
serum total cholesterol, serum LDL cholesterol, seated SBP, change in SBP
and DBP during the ultrasound examination, body mass index, and smoking
status, measures of those risk factors were averaged over Exam 1 and Exam
3. For those subjects with missing measures in Exam 3 (n=92), their values in
Exam 1 are taken as the average. It was these averaged values that are used
in further analysis.
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2.3 Statistical Models
a) Linear relationship,
The relationship between IMT and changes in SBP, DBP, and HR
during ultrasound examination were analyzed in a straight-forward linear
regression:
IMT = a + Pt X + covariates + C ,
where X is the variable to be studied (ASBP, ADBP, AHR, AMAP, APP, etc),
covariates include age, body height, total cholesterol, average SBP, ethnic
group (Non-Hispanic White, Hispanic, African American, Asian, Other), body
height, body mass index, smoking status (current, former, never), diabetes
(NIDDM or IDDM/other), and use of medication for hypertension (yes/no) and
hypercholesterolemia (yes/no). When women and men were analyzed
together, sex was also used as a model covariate.
b) Analysis of interactive effects
Generally speaking, two separate models were employed to assess the
possible interaction of LDL and a moderating variable (SBP, ASBP, or
Smoking Status) with IMT/AIMT. The first model was employed to calculate
the linear trend of the relationship between IMT/AIMT and LDL in sub-groups
of subjects defined by the moderating variable. As described in Table 1, a
17
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linear regression is conducted with IMT/AIMT being the dependent variable,
LDL, dummy variables of the moderating variable, interaction terms between
LDL and the moderating variable, and other covariates as the independent
variables. The covariates included age, seated SBP/smoking status (when
they are not the moderating variable), ethnic group (Non-Hispanic White,
Hispanic, African American, Asian, Other), body height, body mass index,
diabetes (NIDDM or IDDM/other), use of medication for hypertension (yes/no)
and hypercholesterolemia (yes/no), and, in AlMT related analysis, follow-up
duration also.
The second model was designed to depict the general relationship
between IMT/AIMT and LDL, by a moderating variable. Within each smoking
status, least square means of adjusted IMT/AIMT were calculated in quintile
groups of LDL-C. The graphical presentation of the results involved the
plotting of average adjusted IMT/AIMT verse the median of LDL in each of the
15 sub-groups (5 quintile of LDL x 3 sub-groups defined by the moderating
variable). The general relationship between LDL and IMT/AIMT could then be
visualized by connecting the average adjusted IMT in each of the 3 sub
groups defined by the moderating variable. The covariates are the same as in
model 1.
18
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Table 1: Analysis of Interactive effects
To study possible moderation of the dependency of IMT/AIMT on LDL by a
moderating variable X2(eg. sbp) dummy variables will be generated for the
moderating variable X2, linear interaction terms will be constructed
between the study variable and the dummy variables. The detail for the
second interaction analysis is presented below.
X 2 Tertile Value of Dummy Variables_________
—22
X2!LDLm X^LDL,
Low 1 0 LDLm 0
Middle 0 1 0 l d l m
High 0 0 0 0
The regression equation to estimate the interactive effect was specified as
IMT/AIMT= a + P,X2 1 +£2X2, + p3 X2 1 LDLM + P ^LD L m +p5 LDLM + (cov) + q
where p5 is the slope of IMT on LDLM in the high X2 group, p3is the
difference between the slope of IMT on LDLM in the high and low X2
groups, p4is the difference between the slope of IMT on LDLM in high and
middle X2 groups.
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3 Results
3.1 The Interaction of LDL and SBP with IMT/AIMT
Table 2 summarizes descriptive statistics of the cross-sectional sample
at Exam 1 by sex and tertiles of SBP. Due to stratified sampling, the
prevalence of current smokers and Hispanics is about twice that in the
employee population from which the cohort was sampled. Note that the high
SBP tertile includes a greater proportion of persons with diabetes and a larger
percentage of subjects who used medication to treat hypertension or
hypercholesterolemia. As expected, within men or women, body mass index
was larger when SBP was higher. The within sex distribution of other
covariates such as age, body height, smoking status were comparable
between Low, Middle, and High SBP groups.
Figure 6 depicts the relations between IMT and LDL quintiles by SBP
tertile. It is clearly shown that there is no significant linear trend in IMT across
LDL quintiles in the low (p=-0.003±0.009 mm/mmol/L, p=0.78) and middle (p=-
0.006+0.008 mm/mmol/L, p=0.51) SBP tertile groups. However, there is an
upward trend (P=0.028±0.008 mm/mmol/L, p= 0.0006) in IMT with increasing
LDL in the high SBP tertile. The slope in the high SBP group was significantly
greater than the slope in the middle (p=0.004) and low (p=0.011) SBP groups.
20
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Table 2: Summary of Related Variables by Sex and by SBP Tertile Groups
Variables
Women
Tertiles of SBP
Men
Tertiles of SBP
Low Middle High Low Middle High
N 82 79 80 88 84 84
SBP [min-max] [93-120] [121-132] [133-173] [102-123] [124-131] [132-175]
Ethnic Groups (%)
Non-Hispanic White 56.1 49.4 61.3 51.1 56.0 50.0
Hispanic White 25.6 32,9 21.3 31.8 27.4 41.7
African American 6.1 6.3 7.5 8.0 3.6 2.4
Asian 11.0 11.4 7.5 5.7 7.1 2.4
other 1.2 0.0 2.5 3.4 6.0 3.6
Smoking Status (%)
Current 20.7 11.4 25.0 34.1 26.2 35.7
Former 31.7 31.7 23.8 28.4 36.9 31
Medication (%)
Hypertension 4.9 12.7 37.5 2.3 11.9 22.6
Hypercholesterolemia 0,0 1.3 7.5 5.7 3.6 10.7
Diabetes (%) 0.0 1.3 3.8 2.3 2.4 3.6
IMT (mm) 0.615±0.056 0.642±0.071 0.69410.100 0.63110.083 0.67810.100 0.71310.112a
AGE (yr.) 50.5±3.8 51.3±4.0 53.114.9 48.114.4 49.114.8 49.215.1
Body Height (m) 1.61 ±0.06 1.62±0.07 1.6210.08 1.7610.07 1.7610.07 1.7610.07
Body Mass Index (kg/m2) 24.8±4.5 27.515.7 28.416.4 26.313.5 28.814.2 29.415.2
SBP (mmHg) 110.5±6.5 126.513.2 145.319.4 117.314.9 127.312.3 143.4110.7
LDL (mmol/L) 3.117±0.768 3.09710.915 3.49410.876 3.55610.902 3.52610.805 3.86810.953
a : MEANlSD
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Figure 6: Carotid Artery IMT with LDL-CHOL, By SBP, All Subjects
0.8
0.78
0.76
0.74
0 0.72
1 °-7
H 0.68
§ 0.66
0.64
0.62
0.6
0.58
1.8 2.3 2.8 3.3 3.8 4.3 4.8 5.3
LDL-Chol (mmol/L)
- SBP Low (93-122) —A - SBP Medium (1 2 3 -1 3 1 )- * - S B P H igh(132-175)
Adjusted for age, sex, body height, race, body mass index, smoking status, diabetes, medication
status for hypertension and hypercholesterolemia
to
N 3
Similar analyses were performed in women, and men separately, and
excluding diabetic subjects or persons taking medications for hypertension or
hypercholesterolemia. The results are summarized in Table 3, listed in the
upper portion of the table was the results generated from the analysis with
continuous LDL-C, and listed in the lower portion of the table are the results
generated from median substituted LDL-C. It was believed that to substitute
the raw continuous values of LDL-C with the median in each of the 3 (SBP
groups) x 5 (LDL-C groups) = 15 sub-groups might adjust for the impact of the
extreme values of LDL-C. Note that the pattern of increased slope in the high
SBP group is similar within each of the 6 study samples. Such as, in the sub
set of 405 subjects (sample CA2) without diabetes or treatment for
hypertension or hypercholesterolemia, IMT was significantly related to LDL
only in the high SBP tertile (p=0.021 ±0.009 mm/mmol/L, p= 0.017). These
slopes were not significant in the middle (p=-0.004±0.009 mm/mmol/L, p=
0.61) or low (p=-0.005±0.010 mm/mmol/L, p= 0.64) SBP tertiles, and the
interaction terms were significant for both the middle (p=0.03) and low
(p=0.05) SBP tertiles.
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Table 3: Cross-sectional Linear Relationshipa between IMT and LDL Cholesterol, by SBP Tertile Group
SBP Low
N BETA ± se
Pe
SBP Middle
N Beta ± Se
Pe
N beta
SBP High
± se
Pe
Pe
H vs. L
for diff
H vs. M
Continuous0
C A b 170 -0.002 ± 0.008 0.764 158 -0.002 ± 0.007 0.727 169 0.020 ± 0.007 0.003 ** 0.026 * 0.018*
C W b 82 -0.013 ± 0.010 0.216 79 -0.017 ± 0.009 0.061 + 80 0.017 ± 0.010 0.093 + 0.042 * 0.012*
C M b 88 0.013 ± 0.010 0.219 84 0.010 ± 0.012 0.426 84 0.022 ± 0.010 0.035 * 0.542 0.426
C A 2 b 138 -0.006 ± 0.009 0.508 128 -0.003 ± 0.008 0.692 139 0.020 ± 0.008 0.012 * 0.027 * 0.032 *
C W 2b 62 -0.009 ± 0.011 0.412 63 -0.012 ± 0.011 0.261 67 0.013 ± 0.011 0.221 0.146 0.096 +
CM2 b 68 0.010 ± 0.014 0.468 78 0.002 ± 0.012 0.852 67 0.015 ± 0.011 0.175 0.791 0.422
Median
d
C A b 170 -0.003 ± 0.009 0.776 158 -0.006 ± 0.008 0.509 169 0.028 ± 0.008 0.001 *** 0.011 * 0.004 **
C W b 82 -0.010 ± 0.011 0.361 79 -0.014 ± 0.011 0.196 80 0.022 ± 0.012 0.068 + 0.053 * 0.026 *
CM b 88 0.016 ± 0.013 0.231 84 0.009 ± 0.013 0.514 84 0.031 ± 0.011 0.008 ** 0.387 0.204
CA2 b 138 -0.005 ± 0.010 0.640 128 -0.004 ± 0.009 0.613 139 0.021 ± 0.009 0.017* 0.050 * 0.035 *
CW2 b 62 -0.008 ± 0.012 0.466 63 -0.018 ± 0.012 0.151 67 0.016 ± 0.014 0.258 0.180 0.071 +
CM2 b 68 0.015 ± 0.016 0.342 78 0.000 ± 0.014 0.981 67 0.017 ± 0.012 0.142 0.918 0.342
Notes:
a: Adjusted for age, body height, race, smoking status, body mass index, for sample CA, CW, and CM, additional
covariates include diabetes, and medication for hypertension or hypercholesterolemia. For analysis with women and
men combined (sample CA and CA2), sex was also adjusted,
b: CA: all women and men, CW: ail women, CM: all men. CA2, CW2, and CM2: sub-group of CA, CW, and CM separately,
excluding subjects with diabetes, and those who took medications against hypertension and hypercholesterolemia.
c : Raw LDL-C measures were used in the regression, metric for beta and se in table: mm/mMol/L
d : Continuous LDL-C were replaced by the median in each of the 5 x 3=15 sub-groups defined by LDL-C quintiles and SBP
tertiles
e: significance level in 2-tailed t-test: +: p<0.10, * : p<0.05, **: p<0.01
N J
The findings were also comparable when using total cholesterol instead
of LDL in the previous analysis. For all men and women (N=497), IMT was
significantly related to total cholesterol only in the high SBP tertile
group(p=0.021+0.008 mm/mmol/L, p= 0.006). These slopes were not
significant in the middle (p=-0.007±0.008 mm/mmol/L, p= 0.42) or low (p=-
0.007+0.008 mm/mmol/L, p= 0.40) SBP tertile groups, and the interaction
terms were significant between high SBP tertile and both the middle (p=0.01),
or low (p=0.01) SBP tertiles.
The linear relationship between high-density lipoprotein and IMT was
not significant in Low (p=0.009±0.019, p=0.64), middle (p=-
0.009±0.023,p=0.69), or high (p=-0.020±0.023,p=0.38) SBP tertile groups.
None of the linear slopes were significantly different from each other.
Similar analyses of LDL and DBP yielded results in the same direction.
When subjects were stratified into 3 groups based on DBP tertile (low [67-85
mmHg], middle [86-92 mmHg], high [93-128 mmHg]), IMT was shown to be
significantly related with LDL in high DBP tertile group (p=0.024±0.008
mm/mmol/L, p= 0.005), but not in middle DBP tertile group (P=0.012±0.008
mm/mmol/L, p= 0.17) or low DBP tertile group (P=-0.005±0.009 mm/mmol/L,
p= 0.59). The linear slope in high DBP tertile is significantly higher (p=0.02)
25
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than the slope in low DBP tertile, although not statistically different than that of
the middle tertile (p=0.30).
Longitudinal relationship with AIMT over 18 months were analysed
using 414 subjects with complete measures. Table 4 summarizes the
descriptive statistics of the study variables by tertiles of SBP. As a
comparison, the descriptive statistics of these variables within the subjects
excluded (due to attrition to follow-up, or incomplete measures) from the
analysis is also listed in Table 4. The high prevalence of current smokers and
Hispanics is due to stratified sampling with higher sampling rates. The high
SBP tertile group includes a greater proportion of persons with diabetes and
treatment for hypertension and hypercholesterolemia, serum LDL-C is
elevated in this group. The data indicated that AIMT were comparable in low,
middle SBP tertile groups, and in the subjects excluded from the present
analysis, while AIMT was highest in the high SBP tertile group.
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Table 4. Summary of Study Variables in 414 Subjects in Longitudinal Analysis, by SBP Tertile Groups
SBP Averaged over Exam 1 and Exam 3 Excluded Sub.
Variables Low(n=138) Middle (n=141) High (n=135) n=162
SBP [min-max] (mmHg) [95-121] [122-131] [132-182] [106-159]
MEN (%) 44.9 58.6 52.6 55.8
Ethnic Groups (%)
Non-Hispanic White 49.3 57.9 51.9 60.1
Hispanic White 32.6 26.4 31.9 29.4
African American 6.5 5.7 5.2 4.3
Asian 8.7 7.9 7.4 4.9
Other 2.9 2.1 3.7 1.2
Smoking Status (%)
Current at Exam 1 26.1 24.3 23.7 35.6
Former at Exam 1 28.3 28.6 34.1 30.7
Current at Exam 3 22.5 22.9 20.7 (73)a 38.4
Former at Exam 3 31.9 28.6 35.6 (73) 26.0
Medication (%)
Anti-hypertension Exam 1 2.9 8.6 34.8 18.4
Exam 3 2.0 6.2 17.3 17.5
Anti-hypercholesterolemia Exam 1 1.4 4.3 7.4 11.7
Exam 3 0.7 4.1 7.3 20.0
ADIABETE (%) 0.0 2.9 4.4 4.3
AGE (yr) 49.1 ±4.3b 50.3 ±4.9 50.6 ±4.9 50.2 ±4.7
Body Height (m) 1.675 ±.089 1.706 ±.097 1.689 ±.109 1.701 ±.1
Duration from Exam 1 to Exam 3 558.6 ±77.4 568.0 ±81.3 571.8 ±82.3 (73) 559.6 ±91.5
IMT between Exam 1 and Exam 3 0.013 ±.035 0.012 ±.036 0.021 ±.047 (67) 0.013 ±.053
to be continued
to
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Table 4 continued from previous page
Variables
Tertiers o f SBP Averaged over Exam 1 and Exam 3 Excluded Sub.
N=163 Low (n=138) Middle (n=140) High (n=135)
SBP [min-max] (mmHg) [95-121] [122-131] [132-182]
Body mass index (Kg/m2 )
Exam 1 25.6 ±4.0b 27.5 ±5.0 30.0 ±6.3 28.6 ±5.5
Exam 3 26.0 ±4.1 27.7 ±5.1 30.2 ±5,9 (73 )a 30.9 ±6.0
Average 25.8 ±4.0 27.6 ±5.0 30.1 ±6.0 28.7 ±5.5
Total serum cholesterol (mmol/L)
Exam 1 5.363 ±.868 5.481 ±.926 5.657 ±.956
Exam 3 (121 )a 5.434 ±.966 (128) 5.491 ±1.034 (119) 5.646 ±.993 N/A
Average 5.377 ±.856 5.480 ±.92 5.643 ±.881
Fasting serum LDL-C (mmol/L)
Exam 1 3.281 ±.860 3.441 ±.906 3.576 ±.914
Exam 3 (115) 3.462 ±.944 (123) 3.609 ±.949 (111) 3.710 ±.885 N/A
Average 3.356 ±.836 3.508 ±.871 3.613 ±.832
SBP (mmHg)
Exam 1 114.5 ±7.5 126.6 ±4.8 142.6 ±11.8 131.2 ±14.9
Exam 3 113.3 ±6.6 126.1 ±5.4 142.3 ±11.7 (73) 131.7 ±13.8
Average 113.9 ±5.4 126.3 ±2.8 142.5 ±9.8 131.2 ±13.9
DBP (mmHg)
Exam 1 82.8 ±6.6 89.4 ±6.3 96.8 ±8.3 91.6 ±10.2
Exam 3 79.3 ±6.8 86.6 ±7.3 94.4 ±9.2 (73) 89.7 ±9.9
Average 81.1 ±6.0 88.0 ±6.1 95.6 ±7.8 91.1 ±9.3
a: n u m b er o f subjects w ith v alid m easu re for this p artic u la r variable
b: m ean ± S D
r o
c o
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Figure 7: 18 Month Carotid Artery IMT Progression with LDL-CHOL, By SBP
0.055
0.045
f 0.035
0.025
o
< D
O O
a
at
XI
U
0.015
0.005
-0.005
-0.015
1.8 2.8 4.8 2.3 3.3 3.8 4.3 5.3
LDL-Chol (mmol/L)
- ♦ - SBP Low (95-121) — A - SBP Medium (122-131) SBP High (132-182)
Adjusted for age, sex, body height, race, body mass index, smoking status, diabetes, medication
status for hypertension and hypercholesterolemia, and duration between Exam 1 and Exam 3
to
c o
Figure 7 depicts the relations between AIMT and LDL quintiles by SBP
tertile, as generated from model 2. The linear trends were computed in model
1. There is no significant linear dependency of AIMT on LDL-C in the low (p=-
0.005±0.005 mm/mmol/L, p=0.34) and middle (p=-0.006±0.005 mm/mmol/L,
p=0.19) SBP tertile groups. However, there is an upward trend
(P=0.012±0.005 mm/mmol/L, p= 0.012) in IMT with increasing LDL in the high
SBP tertile. The slope in the high SBP group was significantly greater than the
slope in the middle (p=0.006) and low (p=0.01) SBP groups. Similar analyses
were also conducted in 5 sub samples. As listed in Table 5, although not as
significant, the previous pattern of relationships holds well in each of the
analyses, especially among men (sample LM and LM2).
The findings were comparable when using total cholesterol instead of
LDL in the previous analysis. For all men and women (N=414), IMT was
significantly related to total cholesterol only in the high SBP tertile group
(P=0.012±0.005 mm/mmol/L, p= 0.01). These slopes were not significant in
the middle (P=-0.005±0.004 mm/mmol/L, p= 0.19) or low (P=-0.005±0.005
mm/mmol/L, p= 0.28) SBP tertile groups, and the interaction terms were
significant between high SBP tertile and both the middle (p=0.005), or low
(p=0.01) SBP tertiles.
30
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Table 5. Longitudinal Linear Relationship3 between 18 Months AIMT and LDL Cholesterol, by SBP Tertile Group
SBP Low
N BETA ± se
Pe
N
SBP Middle
beta ± se
Pe
N
SBP High
beta ± se
Pe
p e for diff
H vs. L H vs. M
C ontinuousc
L A b 138 -0.0027 ± 0.0041 0.520 141 -0.0054 ± 0.0039 0.168 135 0.0090 ± 0.0042 0.033 * 0.046 * 0.011*
L W b 66 -0.0042 ± 0,0073 0.568 66 0.0014 ± 0.0049 0.775 67 0.0091 ± 0.0062 0.147 0.172 0.331
L M b 69 -0.0036 ± 0.0058 0.529 75 -0.0108 ± 0.0062 0.086 71 0.0092 ± 0.0061 0.135 0.131 0.022 *
LA 2 b 115 -0.0062 ± 0.0050 0.221 109 -0.0001 ± 0.0042 0.984 115 0.0005 ± 0.0042 0.899 0.298 0.915
LW 2b 53 -0.0025 ± 0.0082 0.755 52 0.0085 ± 0.0056 0.132 53 0.0001 ± 0.0062 0.987 0.795 0.314
LM 2b 59 -0.0087 ± 0.0066
M ediand
0.193 64 -0.0074 ± 0.0066 0.260 58 0.0037 ± 0.0064 0.562 0.179 0.226
L A b 138 -0.0048 ± 0.0049 0.335 141 -0.0062 ± 0.0047 0.187 135 0.0120 ± 0.0048 0.012* 0.014 * 0.006 **
L W b 66 -0.0036 ± 0.0077 0.647 66 0.0018 ± 0.0057 0.755 67 0.0074 ± 0.0068 0.280 0.294 0.523
LM b 69 -0.0086 ± 0.0067 0.200 75 -0.0129 ± 0.0073 0.078 + 71 0.0161 ± 0.0071 0.025 * 0.012 * 0.005 **
LA 2b 115 -0.0047 ± 0.0058 0.413 109 -0.0016 ± 0.0045 0.722 115 0.0025 ± 0.0047 0.588 0.320 0.518
LW 2b 53 -0.0048 ± 0.0085 0.575 52 0.0061 ± 0.0067 0.366 53 -0.0003 ± 0.0070 0.966 0.686 0.510
LM 2 b 59 -0.0110 ± 0.0070 0.119 64 -0.0103 ± 0.0074 0.167 58 0.0124 ± 0.0073 0.091 + 0.022 * 0.031 *
Notes:
a: Adjusted for age, body height, race, smoking status, body mass index, follow-up duration, for sample LA, LW, and LM,
additional covariates include diabetes, and medication for hypertension or hypercholesterolemia. For analysis with
women and men combined (sample LA and LA2), sex was also adjusted,
b: LA: all women and men, LW: all women, LM: all men. LA2, LW2, and LM2: sub-group of LA, LW, and LM separately,
excluding subjects with diabetes, and those who took medications against hypertension and hypercholesterolemia.
c : Raw LDL-C measures were used in the regression, metric for beta and se in table: mm/mMol/L
d : Continuous LDL-C were replaced by the median in each of the 5 x 3=15 sub-groups defined by LDL-C quintiles and SBP
tertiles
e: significance level in 2-tailed t-test: +: p<0.10, * : p<0.05, **: p<0.01
3.2 Short Term Change in SBP,DBP, and HR and IMT
Change in SBP/DBP/HR was calculated as the difference of
SBP/DBP/HR before and after ultrasound examination. The possible
measurement error made it difficult to test the possible effects on AIMT, the
study was focused on IMT only.
T able 6: U n iva ria te S u m m a ry o f C ardiac R eactivity d u rin g U ltra s o u n d E xam ination
W om en (N=264) Men (N=299)
Mean SD Min Max Mean SD Min Max
SBP
(mmHg)
Before 123.27 14.85 90.00 169.00 125.00 13.11 96.50 177.50
After 121.66 14.45 89.00 168.50 122.27 11.93 91.50 169.00
Change -1.63 5.32 -24.00 13.00 -2.76 5.37 -25.00 10.00
DBP
(mmHg)
Before 80.49 9.72 52.50 107.00 83.57 9.45 51.50 117.50
After 79.78 9.25 48.50 104.50 82.05 8.98 56.00 121.00
Change -0.71 3.95 -11.50 14.00 -1.57 3.77 -16.00 13.50
MAP
(mmHg)
Before 94.75 10.46 68.00 127.00 97.38 9.91 74.17 137.50
A fter 93.74 10.09 64.17 122.17 95.45 9.26 76.17 137.00
Change -1.01 3.51 -11.33 10.17 -1.93 3.54 -15.33 9.83
PP
(mmHg)
Before 42.77 11.06 16.00 88.50 41.43 9.13 21.00 80.00
After 41.88 10.57 17.00 89.00 40.22 8.33 14.00 65.50
Change -0.89 5.90 -22.00 22.00 -1.20 5.66 -22.00 15.00
HR
(beat/min)
Before 78.32 9.50 56.00 108.00 76.76 9.76 54.00 104.00
A fter 72.53 8.60 52.00 100.00 69.95 8.52 52.00 94.00
Change -5.79 5.32 -22.00 12.00 -6.81 5.76 -28.00 8.00
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Table 6 lists the summary of blood pressures, heart rates before and
after the ultrasound examination, and their changes. The average SBP
change during the resting period was -1.632 mmHg for women and -2.761
mmHg for men. The average DBP change was -0.715 mmHg for women and
-1.569 mmHg for men. The average HR change was -5.788 bpm for women
and -6.809 bpm for men. During the ultrasound examination, SBP dropped in
63.4% of subjects, DBP dropped in 60.9%, while heart rate decreased in most
of the subjects (84.5%).
The results from model 1 for general relationships are depicted in
Figures 8, 9, and 10 for change in SBP, DBP, and heart rate, separately. The
results from model 2 are summarized in Table 7. Combining the graphical
presentations and the quantitative computations of the linear relationship, It is
apparent that IMT is not related to ASBP in either women or men.
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Table 7: Linear Effects a (P±SE) of Change in SBP, DBP, and Heart
Rate during Ultrasound Examination on IMT (mm).
Women Men All Subjects
ASBP
(mmHg)
0.0006+0.0009
p=0.47
0.0016±0.0010
p=0.14
0.0010±0.0007
p=0.13
ADBP
(mmHg)
0.0038±0.0012
p=0.0016 **
0.0028±0.0015
p=0.06 +
0.0033±0.0009
p=0.0005 ***
AMAP
(mmHg)
0.0036±0.0013
p=0.007 **
0.0036±0.0016
p=0.026 *
0.0036±0.0010
p=0.0007 ***
APP
(mmHg)
-0.0012±0.001
p=0.14
0.0001 ±0.0010
p=0.91
0.0006±0.0006
p=0.32
AHR
(beat/min)
0.0021 ±0.0009
p=0.014 *
-0.0005±0.0010
p=0.57
0.0006+0.0007
p=0.39
A(HR*SBP)
(100 bpm * m m Hg)
0.0014+0.0006
p=0.013 *
-0.0001 ±0.0001
p=0.89
0.0006±0.0004
p=0.16
A(HR*DBP)
(100 bpm * m m Hg)
0.0033±0.0008
p=0.0001 ’ **
-0.0001±0.0001
p=0.87
0.0014±0.0006
p=0.02 *
Notes:
a: adjusted fo r age, body height, race, average SBP, body m ass index, total cholesterol,
smoking status, diabetes, and medication for hypertension or hypercholesterolem ia. For
analysis with w om en and men combined , sex was also adjusted.
+:p<0.10, * : p<0.05, ** : p<0.01, ***: p<0.001
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Figure 8: Carotid Artery IMT with ASBP During Ultrasound Scanning
0.71
0.7
0.69
0.68
£ 0.67
S 0.66
§> 0.65
£ 0.64
0.63
Women - A - Men
0.62
0.61
-10 -8 -6 -4 -2 0 2 4 6
Change of SBP (mmHg)
A djusted for age, sex, body height, race, sm oking status, body m ass index, SBP, total
cholesterol, diabetes, m edication status for hypertension and hypercholesterolem ia
C O
CJ I
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Figure 9 : C aro tid A rtery IM T w ith A D BP D u rin g U ltraso u n d S can n in g
0.71
0.7
0.69
0.68
H 0.67
B 0.66
& 0.65
£ 0.64
<
0.63
Women * a - Men
0.62
0.61
6 -4 •2 0 2 4
Change of DBP (mmHg)
Adjusted for age, sex, body height, race, smoking status, body mass index, SBP, total
cholesterol, diabetes, medication status for hypertension and hypercholesterolemia
c o
O )
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Figure 10: Carotid Artery IMT with AHR during Ultrasound Scanning
0.71
0.7 Women - A - Men —
0.69
| 0.68
H 0.67
§ 0.66
§> 0.65
0.64
U
U
3
0.63
0.62
0.61
-13 -15 -11 ■ 9 ■ 7 •5 ■ 3 1 1
Change of Heart Rate (Beat/Min)
Adjusted for age, sex, body height, race, smoking status, body mass index, SBP, total
cholesterol, diabetes, medication status for hypertension and hypercholesterolemia
t o
Table 8. Univariate Summary of Study Variables, by Tertile Group of Change in SBP
during Ultrasound Examination
High M iddle Low
ASB P(m m H g) (-2 5 --5 mmHg) (-4 .5 - -0.5 (0.0,10.0 mmHg)
_______________________ m m Hg)______________________
N 80 90 86
DIABETE (%) 2.5 3.3 2.3
Smoking Status (%)
C urrent E1 37.50 36.67 22.09
E 3 a 29.23 30.95 17.65
Form er E 1 31.25 28.89 36.05
E 3 a 35.38 32.14 39.71
Medication Status (%)
Hypertension E 1 12.50 8.89 15.12
E 3 a 10.77 5.95 7.35
Hypercholesterolem ia E 1 8.75 7.78 3.49
E 3 a 6.15 2.38 2.94
R a ce (%)
Non-Hispanic W HITE 51.25 58.89 46.51
Hispanic 36.25 26.67 38.37
African Am erican 3.75 5.56 4.65
ASIAN 3.75 5.56 5.81
O THER 5.00 3.33 4.65
AGE (yr) 49.75 ± 4.43 b 48.16
±
4.62 48.48 ± 5.13
Body Height (m) 1.75 ± 0.07 1.77 ± 0.07 1.76
+
0.07
Body Mass Index (Kg/M A2) 28.40 ± 4.22 28.08 ± 4.76 28.28 ± 4.42
Before-Resting DBP (m m Hg) 85.54 ± 11.20 81.48
+
8.14 82.64
+
9.10
Resting DBP (mmHg) 83.23 ± 10.10 80.19
+
7.97 82.02
+
9.31
IMT (mm) 0.694 ± 0.098 0.678 ± 0.112 0.664
+
0.107
LDL (mMol/L) 3.804 ± 0.840 3.655 ± 0.860 3.655
+
0.837
Before-Resting SBP (m m Hg) 131.24 ± 15.55 122.68
±
10.71 119.59
±
10.10
Resting SBP (m m Hg) 122.54 ± 14.62 120.27
+
10.67 122.37
±
10.76
Notes:
a : N for Exam 3 m easures in Low, Middle, and High ASBP groups w ere 68, 84, 65,
separately.
b: mean ± SD
38
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IMT was strongly positively related with ADBP in women (p=0.0038±0.0012
mm/mmHg, p<0.0014), and moderately related to ADBP in
men.(p=0.0027±0.0015, p<0.07) Combining women and men, the
significance level for the relationship between IMT and ADBP was even higher
(p=0.0005). IMT was also positively related to change in heart rate in women
(p=0.0021 ±0.0009 mm/beat/min, pO.014), but not in men. Also listed in
Table 7 are the results on change in mean arterial pressure (AMAP), change
in pulse pressure (APP), and change in double products (A hr*sbp, A hr*dbp).
In women but not in men, all except APP were positively related to thicker
IMT.
The univariate summary of IMT and other study variables are listed in
Table 8, by ASBP tertile groups. Resting SBPs were similar across the three
ASBP groups. ASBP were different mainly because the before resting SBP
were different across these three groups. As shown in figure 11, when
adjusted for resting SBP and other covariates, the dependency of IMT on LDL
was found to be different in different tertile groups of change in SBP in men.
Those men whose SBP dropped the most (-25, -5 mmHg) had a significantly
positive dependency of IMT on LDL (p=0.037±0.012 mm/mmol/L, p=0.002),
while there were no significant relationship between IMT and LDL in the other
two tertile groups of ASBP (p=-0.001±0.011 mm/mmol/L, p=0.95 for the
39
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middle (-4.5, -0.5 mmHg) group, (0=0.004+0.012 mm/mmol/L, p=0.77 for the
low (0.0, 10 mmHg) group. The dependence of IMT on LDL was significantly
different between high and middle ASBP groups (p=0.02), and high and low
ASBP groups (p=0.05).
The possible associations between conventional risk factors of
atherosclerosis and cardiac reactivity during ultrasound examination were also
investigated. Table 9 lists the Pearson correlation between CV and other
variables, by sex. Age was negatively related to ASBP in men. Current
smoking was also negatively correlated with ASBP and AHR in men.
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Table 9. Pearson Correlation (corrr/p) between Study
Variables and change in SBP, DBP, and Heart Rate during Ultrasound
Examination, by Sex
Women (N=264) Men (N=299)
ASBP ADBP AHR ASBP ADBP AHR
AG E -0.028
0.652
-0.158
0.010 *
0.008
0.897
-0.156
0.007
-0.104
** 0.074
0.014
0.804
C urrent Sm oking -0.031
0.621
-0.023
0.710
0.042
0.498
-0.120
0.039
0.015
* 0.802
-0.179
0.002 **
Serum LDL-C 3 -0.046
0.474
-0.006
0.922
-0.029
0.655
-0.101
0.108
-0.040
0.527
-0.076
0.223
Serum HDL-C 0.102 0.032 -0.009 0.000 -0.013 0.075
0.099 + 0.600 0.884 0.995 0.818 0.195
Serum T riglycerides 3 -0.041 -0.022 0.033 -0.041 -0.089 0.022
0.529 0.737 0.610 0.513 0.156 0.722
Resting SBP 0.111
0.072 +
0.008
0.899
0.085
0.168
-0.012
0.837
-0.088
0.128
0.006
0.916
Resting DBP -0.017
0.779
0.090
0.143
-0.036
0.562
-0.047
0.414
0.090
0.120
-0.062
0.287
Note:
3: from fasting sam ple, N=241 for women, N=256 for men
+ :p< 0.1 0, * : p<0.05, **:p < 0 .0 1 , ***: p<0.001
41
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Figure 11 : C arotid A rtery IM T w ith LDL-CHOL, B y A SB P,
M en O nly (sam ple CM)
0.76
0.74
0.72
0.7
0.68
0.66
0.64
0.62
0.6
2.3 2.6 2.9 3.2 3.5 3.8 4.1 4.4 4.7 5
LDL-Chol (mmol/L)
— DSBP Low [-25,-5] - A - DSBP Medium (-5,0) - * - DSBP High [0,10]
Adjusted for age, sex, body height, race, body mass index, during resting SBP,
smoking status, diabetes, medication status for hypertension and hypercholesterolemia
to
3.3 The Interaction of LDL and Cigarette Smoking with IMT and AIMT
The within sex and smoking status summary of relevant variables are
presented in Table 10. The sample for cross-sectional study with all sexes
(CA) is composed of 241 women and 256 men of multiple races. Because of
over-sampling of Hispanic Whites and current cigarette smokers, their
proportion in the sample were larger than in the general population. Average
(mean±se) pack-years of smoking is 23.38±1.88 in women and 26.55±1.41 in
men (p=0.18 for sex difference). The average age of the subjects was 51.6
year for women and 48.8 year for men. Overall, 2.2% of the subject had
diabetes (NIDDM or IDDM/other) at Exam 1, 15.1% of the subjects were
taking medication for hypertension, 4.8% of the subjects were users of lipid
lowering drugs. As depicted in Figure 12, IMT in current smoking men was
thicker than in former smokers (p=0.003 in Exam 1, p=0.03 in Exam 3), and
those who never smoked (p=0.0001 in both Exam 1 and Exam 3); however, in
women, there was no statistical difference in age adjusted IMT across
smoking status. There was no age adjusted 18 month AIMT across smoking
status in woman or men.
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Table 10. Summary of Relevant Studying Variables, by Sex and Smoking Status
Variable
W om en Men
Current (N =46) Form er (N =70) N ever (N =125) Current (N =82) Form er (N =82) N ever (N =92)
M ean SD Mean SD M ean SD M ean SD M ean SD M ean SD
Race
Non-Hispanic White 80.4% 57.1% 45.6% 69.5% 48.8% 40.2%
Hispanic 10.9% 25.7% 32.8% 18.3% 39.0% 42.4%
African American 4.3% 11.4% 4.8% 4.9% 3.7% 5.4%
ASIAN 4.3% 2.9% 16.0% 3.7% 4.9% 6.5%
Other 0.0% 2.9% 0.8% 3.7% 3.7% 5.4%
Medication
Anti-Hypertension 17.4% 15.7% 20.0% 12.2% 15.9% 8.7%
Anti-hyperlipidemia 4.3% 1.4% 3.2% 7.3% 7.3% 5.4%
Diabetes 2.2% 1.4% 1.6% 3.7% 2.4% 2.2%
Baseline Average IMT (mm) 0.652 0.079 0.647 0.083 0.651 0.087 0.717 b 0.107 0 .6 6 7 b 0.105 0 .6 4 0 b 0.085
Exam 3 Average IMT (mm) a 0.664 0.084 0.662 0.103 0.662 0.089 0.733 b 0.122 0.688 b 0.119 0.649 b 0.090
18 Month AIMT (mm) a 0.024 0.049 0.020 0.036 0.016 0.032 0.008 0.052 0.020 0.040 0.009 0.034
Age (yr) 50.91 4.57 51.64 4.14 51.91 4.45 50.30 4.77 49.01 4.74 47.16 4.33
Pack-year Smoking (yr*pack/d) 23.38 13.82 9.97 12.12 0.00 0.00 26.55 18.85 12.98 16.15 0.00 0.00
SBP (mmHg) 128.65 17.76 126.14 15.79 127.39 15.27 128.77 12.61 129.41 12.75 129.18 13.02
DBP (mmHg) 87.87 10.64 87.73 8.31 88.58 9.54 91.54 9.33 91.57 8.07 91.38 9.31
BMI (kg/mA 2) 25.55 4.09 27.64 6.08 26.95 6.09 28.13 5.31 29.24 4.09 27.19 3.95
Body Height (m) 1.64 0.06 1.62 0.07 1.61 0.07 1.77 0.06 1.77 0.08 1.75 0.07
HDL Cholesterol (mmol/L) 1.564c 0.383 1.725c 0.334 1.666c 0.378 1.282 0.239 1.267 0.197 1.329 0.221
LDL Cholesterol (mmol/L) 3.331 0.839 3.101 0.726 3.276 0.949 3.797 1.120 3.564 0.618 3.589 0.881
Total Cholesterol (mmol/L) 5.486 0.833 5.322 0.813 5.477 0.980 5.652 1.200 5.502 0.689 5.534 0.916
Notes:
a: N for Exam 3 IMT and AIMT for current, former, and never smokers were 37, 57, and 105 in women, 65, 69, and 81 in men.
b: In men, age adjusted IMT in current smokers was thicker than in former smokers (p=0.003 in Exam 1, p=0.03 in Exam 3), and those who never
smoked(p=0.0001 in both Exam 1 and Exam 3)
c: In women, age adjusted HDL-C was decreased in current smokers (p=.005 vs. former smokers, p=.05 vs. those who never smoked)
s
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Figure 12: Carotid Artery IMT with Smoking Status, By Sex
0.72
0.71
0.7
0.69
0.68
O 0.67
t > Q
S 3 0 -6 6
< 0.65
0.64
0.63
Never Former
Smoking Status
-Women ■ Men
....... T
_ T
r ¥ n
Current
Adjusted for age, sex, body height, race, body mass index, SBP, diabetes, medication
status for hypertension and hypercholesterolemia
• F -
C J l
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Figure 13: Carotid Artery IMT with Cumulative Smoking, By Sex
0.72
0.71
0.7
0.69
0.68
H 0.67
0.66
0.65 «K -
0.64
0.63
0 10 5 15 20 25 30 35 40
Cumulative Smoking (daily Pack * year)
- ♦ - Women 3 K MEN
Adjusted for age, sex, body height, race, body mass index, SBP, diabetes, medication status
for hypertension and hypercholesterolemia
4 *
O )
Figure 13 depicts the relationship between IMT and cumulative pack-year
smoking in men and women, separately, it shows that the positive relationship
between IMT and cumulative smoking are monotonous in men, but IMT is not
related with cumulative smoking in women. As expected, LDL-C is elevated in
current smokers, but it does not achieve statistical significance (current
smokers vs. others: p=.34 in women, p=.15 in men). HDL-C is decreased in
current smoking women (p=0.01 current smoking women vs. other women),
but not in current smoking men (p=0.72 current smoking men vs. other men).
The results from model 1 for general relationships ar summarized in
Table 11 and Table 12. Listed in Table 11 were the cross-sectional
relationships between LDL and IMT in Exam 1, by smoking status and from 6
different samples. Listed in Table 12 were the longitudinal relationship
between LDL and 18 month AIMT assessed by measures in Exam 1 and
Exam 3, by smoking status and from 6 different samples. Six rows in Table
11 and Table 12 listed the relationships in 6 different study samples.
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Table 11. Linear Cross-sectional Relationship between IMT and LDL Cholesterol, by Smoking Status
S am pleb
Smoking Status
p for diff.
Current Former Never
N BETA ± se
P
N beta ± se
P
N beta ± Se P CVS. f cvs. n
CA 128 0.015 ± 0.007 0.034 * 152 -0.003 ± 0.010 0.732 217 0.001 ± 0.006 0.880 0.127 0.139
CW 46 0.029 ± 0.013 0.024 * 70 -0.022 ± 0.012 0.075 + 125 -0.008 ± 0.007 0.248 0.005 ** 0.012*
CM 82 0.008 ± 0.009 0.399 82 0.019 ± 0.016 0.233 92 0.021 ± 0.011 0.068 + 0.353 0.527
CA2 101 0.009 ± 0.007 0.226 126 -0.018 ± 0.011 0.095 + 178 0.004 ± 0.007 0.560 0.037 * 0.652
CW2 36 0.026 ± 0.014 0.066 + 58 -0.021 ± 0.013 0.116 98 -0.003 ± 0.009 0.720 0.016 * 0.082 +
CM2 65 0.000 ± 0.010 0.969 68 -0.014 ± 0.018 0.444 80 0.022 ± 0.013 0.098 0.487 0.187
Notes:
a : Adjusted for age, body height, race, seated SBP, body mass index, for sample CA, CW, and CM, additional covariates
include diabetes, and medication for hypertension or hypercholesterolemia. For analysis with women and men combined
(sample CA and CA2), sex was also adjusted.
b: CA: all women and men, CW: all women, CM: all men. CA2, CW2, and CM2: sub-group of CA, CW, and CM separately,
excluding subjects with diabetes, and those who took medications against hypertension and hypercholesterolemia,
+: p<0.10, * : p<0.05, **: p<0.01 in 2-tailed t-test
00
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Table 12. Linear Longitudinal Relationship between 18 Month AIMT and LDL-C, by Smoking Statusa
S am pleb
Smoking Status
p for diff.
Current Former Never
N BETA ± se
P
N beta ± se
P
N beta ± Se P CVS. f cvs. n
LA 102 -0.004 ± 0.004 0.290 126 0.001 ± 0.005 0.821 186 0.000 ± 0.003 0.993 0.413 0.427
LW 37 0.015 ± 0.007 0.030 * 57 -0.003 ± 0.007 0.657 105 -0.006 ± 0.004 0.173 0.066 + 0.010*
LM 65 -0.008 ± 0.005 0.105 69 0.007 ± 0.008 0.391 81 0.005 ± 0.006 0.395 0.117 0.091
LA2 83 0.000 ± 0.004 0.917 104 -0.006 ± 0.006 0.267 152 -0.002 ± 0.004 0.619 0.386 0.764
LW2 29 0.021 ± 0.007 0.006 * 48 -0.006 ± 0.007 0.393 81 -0.003 ± 0.005 0.523 0.010 * 0.010*
LM2 54 -0.006 ± 0.005 0.249 56 -0.008 ± 0.009 0.426 71 0.001 ± 0.007 0.886 0.859 0.420
Notes:
a : Adjusted for age, body height, race, seated SBP, body mass index, for sample LA, LW, and LM, additional covariates include
diabetes, and medication for hypertension or hypercholesterolemia. For analysis with women and men combined (sample LA
and LA2), sex was also adjusted.
b: LA: all women and men, LW: all women, LM: all men. LA2, LW2, and LM2: sub-group of LA, LW, and LM separately,
excluding subjects with diabetes, and those who took medications against hypertension and hypercholesterolemia.
+: p<0.10, * : p<0.05, **: p<0.01 in 2-tailed t-test
( O
Among women, the relationship between LDL-C and IMT differed by
smoking status: when there was no exclusion for diseased subjects (sample
CW), IMT was positively related to LDL-C in current smokers (p=0.029±0.013
mm/mmol/L, p=0.024), but not in former smokers (P=-0.022±0.012
mm/mmol/L, p=0.08), or those women who never smoked (P=-0.008±0.007
mm/mmol/L, p=0.25); the linear dependency of IMT on LDL was significantly
different between current smokers and former smokers (p=0.005), and
between current smokers and those who never smoked (p=0.01). Similar
results were found from the women excluding diabetes and those who were
taking medication against hypertension and hyperlipidemia (sample CW2).
Longitudinal results listed in Table 12 also revealed similar results in women:
in all women available for the longitudinal analysis (sample LW), LDL-C was
positively related to AIMT in current smokers (p=0.015±0.007 mm/mmol/L,
p=0.03), but not in former smokers (P=-0.003±0.007 mm/mmol/L, p=0.66), or
those women who never smoked (p=-0.006±0.004 mm/mmol/L, p=0.17); the
linear dependency of AIMT on LDL was marginally different between current
smokers and former smokers (p=0.07), and between current smokers and
those who never smoked (p=0.01); Once again, similar findings were found
for those women who were not diabetes and who were not taking medications
for hypertension and hyperlipidemia (sample LW2).
50
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Model 2 generated graphs to depict the general relationships between
IMT/AIMT and LDL within each smoking status. As an example, four figures
are shown to illustrate the detailed within smoking status relationships
between IMT/AIMT and LDL-C. Figure 14 and 15 show the cross-sectional
relationship between Exam 1 IMT and LDL-C in women (sample CW), and
men (sample CM), separately. It can be concluded from Figure 14 that for
women current smokers, although IMT is not elevated, the IMT on LDL slope
for the curve is deeper. On the contrary, as shows in Figure 15, smoking men
had thicker IMT than former or never smokers, but its relation with LDL-C is
not much different from men who are former smokers or never smoked.
Figure 16 and 17 show the longitudinal relationship between 18 month IMT
progression (AIMT) and LDL-C in women (sample LW), and men (sample LM),
separately. It demonstrated that AIMT is positively related to LDL-C only in
current smoking women. To investigate if there is any sex difference between
cigarette smoking and pulse pressure (pp), exam 1 and exam3 average pp
were related to smoking status and exam 1 and exam 3 average pack-year
smoking. Adjusted for age, the correlation between pp and smoking status
(current vs. others) were 0.10 (p=0.14) in women and 0.05 (p=0.44) in men
(p=0.39 for sex difference); the correlation between pp and pack-year smoking
is 0.15 (p=0.02) in women and 0.01 (p=0.91) in men (p=0.03 for sex
difference).
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Figure 14: Carotid Artery IMT with LDL-C, By Smoking Status, Women Only
0.76
0.74
0.72
0.7
| 0.68
H 0.66
£
“ 0.64
0.62
0.6
0.58
2 2.5 3 3.5 4 4.5 5 5.5
LDL-Chol (mmol/L)
Current Smoker - A - Former Smoker — & - Non-Smoker
Adjusted for age, body height, body mass index, race, systolic blood pressure, diabetes,
and medication status for hypertension and hypercholesterolemia
U 1
N >
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Figure 15: Carotid Artery IMT with LDL-C, By Smoking Status, Men Only
0.76
0.74
0.72
^ 0.7
I 0.68
H 0.66
s
“ 0.64
0.62
0.6
0.58 .
2 3.5 2.5 3 4 4.5 5 5.5
LDL-Chol (mmol/L)
Current Smoker - A - Former Smoker — Non-Smoker
Adjusted for age, body height, body mass index, race, systolic blood pressure, diabetes, and
medication status for hypertension and hypercholesterolemia
c n
0 0
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Figure 16: 18 Month AIMT with LDL-C, By Smoking Status, Women Only
S
« * -
o
a >
o >
c
n
j=
o
0.06
0.05
0.04
0.03
0.02
0.01
0
- 0.01
- 0.02
2 2.5 3 3.5 4 4.5 5 5.5
LDL-Chol (mmol/L)
•Current Smoker - A - Former Smoker Non-Smoker
Adjusted for age, body height, body mass index, race, systolic blood pressure, diabetes,
and medication status for hypertension and hypercholesterolemia
(XI
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Figure 17: 18 Month AIMT with LDL-C, By Smoking Status, Men Only
0.06
0.05
| 0-04
H 0.03
|
0.02
O
0 )
o 0.01
c
J S 0
o
- 0.01
- 0.02
2.5 4 2 3 3.5 4.5 5 5.5
LDL-Chol (mmol/L)
Current Smoker - A - Former Smoker —X - Non-Smoker
Adjusted for age, body height, body mass index, race, systolic blood pressure, diabetes,
and medication status for hypertension and hypercholesterolemia
oi
oi
4 Conclusions
Non-invasive ultrasound detection of CCA IMT is an effective tool in the
study of atherosclerosis. Its contribution is obvious in reducing the cost of
epidemiological studies designed to seek the risk factors of
CHD/atherosclerosis. Its role in studying the pathophysiological mechanisms
of early atherosclerosis is unique and indispensable.
Findings from this study can be summarized in the following three
points: 1) In analysis of both cross-sectional and longitudinal data, the
dependency of IMT on LDL-C was shown to be modified by SBP level. The
positive relations between IMT/AIMT and SBP existed only in those women
and men with high SBP. 2) In analysis of cross-sectional data, IMT was
positively related to change in DBP during ultrasound examination in women
and men, IMT was positively related to change in heart rate during ultrasound
examination in women. Furthermore, in men, the dependency of IMT on LDL
was modified by the change in SBP during ultrasound examination. When
adjusted for resting SBP and other covariates, positive relations between IMT
and LDL existed only in those men whose pre-resting SBP was relatively
higher. 3) In men but not in women, IMT is thicker in current smokers;
however, in women but not in men, the dependency of IMT/AIMT on LDL-C is
shown to be modified by smoking status, IMT was positively related to LDL
56
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only in those women who were current smokers, but not in former smoking
women, or those women who never smoked.
The finding that IMT is more strongly related to LDL-C under conditions
of elevated systolic blood pressure is consistent with predictions from the
response-to-injury model of atherogenesis.(45) Elevated blood pressure
induces modifications to the endothelium from may establish the susceptibility
of the artery wall to LDL-induced atherosclerosis.
Similar analysis with total cholesterol or diastolic blood pressure gave
comparable, but less significant findings. Considering the close correlation
between total cholesterol with low density lipoprotein (r=0.68, p=0.0001),
between systolic and diastolic blood pressure (r=0.93, p=0.0001), the data
tended to deliver the impression that low density lipoprotein and systolic blood
pressure were the factors playing central roles in the interactive effects of
lipids and blood pressure on carotid artery intimal-medial thickness.
There are additional aspects of the findings that are suggestive
concerning the pathophysiology of intima-media thickening. As can be seen
in Figure 6, IMT increases substantially from the low to middle SBP tertiles,
even though LDL-induced atherosclerotic thickening in the middle tertile is not
apparent (especially in women). One plausible explanation of this pattern is
that the thickening occurring in the middle SBP tertile is adaptive thickening of
the intima-media complex.(2) Such thickening is characterized by remodeling
57
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to counteract the rise in wall tension. In contrast, maladaptive thickening
involving monocytes recruitment, an inflammatory response with stimulation of
growth factors, proliferation of smooth muscle cells, and lipid accumulation in
the intima more likely occurs in the upper blood pressure group where
endothelial damage is more likely sufficient to initiate atherogenesis. In
addition to inducing the damage that initiates atherogenesis, elevated blood
pressure may also accelerate lipid deposition through continued damage to
the endothelium or increased diffusion of lipoproteins into the subendothelial
space.(90, 91) The combination of elevated serum LDL concentration and
SBP may thus operate synergistically to produce the thickest intima-media
complex.
In the absence of elevated LDL, high blood pressure alone may not
induce maladaptive (atherosclerotic) intima-media thickening.(92) Note in
Figure 6 that the impact of elevated blood pressure on IMT appears to be
limited when LDL is low. This interpretation is supported by findings from
animal models with induced hypertension.(93) It is also consistent with the
fact that in hypertensive patients with low cholesterol levels, left ventricular
hypertrophy is common, but coronary artery disease is not.(94)
This response-to-injury explanation of our findings is indirectly
supported by a comparison of findings from cross-sectional and longitudinal
studies of blood pressure and IMT. In cross-sectional studies, the relationship
58
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between SBP and IMT is generally positive.(35, 49, 95) However, in the few
published longitudinal studies, all(38, 39, 68, 96) buttwo(28, 40) found no
relationship between baseline SBP and subsequent change in IMT.
Interestingly, these two studies that yielded a significant longitudinal
association was among the control group in trials to test the effect of lipid
lowering on IMT progression in hypercholesterolemic subjects. For example,
in KAPS, one of the subject recruitment criteria in baseline was that LDL-C to
be greater than 4 mmol/L.(40) These findings are explained by our model
since only those persons with elevated blood pressure (or some other source
of injury) and elevated LDL would be expected to show atherosclerotic
progression. This pattern of findings from cross-sectional and longitudinal
studies is consistent with a process in which elevated blood pressure leads to
adaptive wall thickening that reaches an equilibrium with the demands of
elevated pressure (rather than continued thickening as in atherosclerosis).
Subsequently, the damaged endothelium induced by the increased pressure
is subject to atherosclerosis if LDL is retained in the artery wall.(97)
Another finding that supports the response-to-injury interpretation of
our results is the regression of carotid artery IMT in lipid lowering trials. In the
ACAPS study,(98) among subjects selected for elevated LDL-C (60th to 90th
percentiles) and carotid lesions, the lovastatin intervention effect in the
hypertensive patients was found to be larger than in the non-hypertensive
59
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patients receiving lovastatin.(28) It could be because the thick carotid wall of
those non-hypertensive patients was not atherosclerotic, its equilibrium
thickness did not depend on plasma LDL level; on the contrary, the thick
carotid wall of the hypertensive patients was atherosclerotic, the wall
thickness would progress/regress more if plasma LDL was higher/lower.
Given that it is the first and only analysis of IMT related data that
revealed such findings, and the observational nature of the other studies cited,
there are clearly alternative explanations of an interaction between SBP and
LDL-C as they relate to carotid IMT. The interaction could arise due to a
synergism of the two factors that does not involve the temporal sequence
inherent in the response-to-injury model or the pressure-adaptive wall
thickening. Elevated blood pressure may, for example, increase the diffusion
of LDL into the subendothelial space,(90, 91) or prolong the retention of LDL
in the intima.(97) Elevated blood pressure could also tend to promote lesions
initiated by elevated LDL-C. Given that SBP and LDL-C tend to be
correlated,(99) it is also plausible that the interaction between the two is due
to each being determined by some other factor(s) that induces
atherosclerosis. The apparent synergism would then actually is due to a third
factor that is indicated by the presence of both risk factors.
There were report of a possible synergism of multiple risk factors to the
existence of collagenous fibrous plaques in the aorta or coronary
60
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arteries.(IOO) Study of 129 autopsied cases in Oslo study revealed an
interactive role of sbp and total serum cholesterol on raised lesions in
coronary arteries,(101) that was in the opposite direction of ours, this
investigators found that the correlation between serum cholesterol and
coronary lesions were 0.485 in the lowest SBP tertile, 0.353 in the middle SBP
tertile, and 0.185 in high SBP tertile. A synergism between SBP and LDL-C
for atherosclerosis is not supported by findings from cohort studies with
coronary symptomatic incident or mortality as endpoints. For example, in the
Honolulu Heart Program, serum cholesterol and systolic blood pressure are
additive (rather than synergistic) in Logistic or Probit models of CHD risk
(unpublished data). Such risk regression models are the equivalent of the
additive form (no interaction) of the linear model with a continuous outcome
such as carotid IMT. However, the absence of synergism between serum
cholesterol or LDL-C and hypertension in cohort studies with CHD endpoints
does not necessarily contradict the injury hypothesis. Event endpoints include
both atherogenic and thrombotic effects of risk factors, and elevated blood
pressure may play a different role in thrombotic events as well as an injury
role in atherogenesis. An example of a potential thrombotic effect of
hypertension is the adverse impact of elevated blood pressure on endothelium
dependent vasodilation and blood rheology, and both of these factors have
been implicated as promoters of the conversion of atherosclerosis to
61
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atherothrombosis.(102)
The complete absence of a positive association between carotid IMT
and LDL-C in the lower blood pressure groups (see Figure 6) is puzzling. If
elevated LDL is sufficient to cause endothelial damage and induce
atherosclerosis,(103) then a positive gradient in these groups would be
expected. However, even if elevated LDL must be preceded by injury in order
to promote atherosclerosis, we might expect that other factors would injure the
arterial wall (that are uncorrelated with LDL-C), and would induce a positive
association. Our findings therefore suggest that elevated blood pressure is
the major source of arterial injury that results in susceptibility to LDL-induced
atherosclerosis. In this regard, note that a small positive gradient in the lower
SBP groups is observed among men, but not among women. This difference
may reflect the greater protection of women against arterial injury from factors
other than blood pressure in this age group.
The finding of a cross-sectional interaction between SBP and LDL-C as
they relate to carotid wall thickness in asymptomatic healthy people is
consistent with predictions of the response-to-injury model of
atherogenesis.(45) Given that this finding has not been reported previously,
and that there are numerous alternative interpretations, replications are
needed to further investigate this issue.
The autonomic nervous system (ANS), especially the sympathetic
62
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nervous system (SNS) and cardiovascular autonomic reflexes, play dominant
roles for acute and chronic control of blood pressure and arterial surface. It is
not exactly known why prolonged or repetitive ANS arousal is related to
atherosclerosis or IMT. One of the postulation is that prolonged or repetitive
ANS arousal may serve as a surrogate measure of the underlying
neuroendocrine exaggerated activities. The effects of neuroendocrine
exaggerated activities on IMT or atherosclerosis may fit into the ‘Response-to-
Injury’ hypothesis of atherogenesis.(45, 46) It has been shown that injured
coronary artery respond differently to intracoronary infusion of
acetylcholine.(83) With the intracoronary infusion of this major ANS neuro
transmitter, atherosclerotic coronary arteries demonstrate a paradoxical
vasoconstriction, while the normal coronary arteries had a dose-dependent
dilation.(83)
Mental stress in the form of a social disruption has been shown to lead
to increased indexes of endothelial dysfunction in monkeys,(84) although the
mechanisms are unknown. Other studies have demonstrated that SNS
stimulation can induce lipid mobilization,(104, 105) elevate blood
pressure(105) and increase platelet aggregation,(106, 107) all contribute to
endothelial injury. O.Donnell et al showed that subcutaneously administered
slow-release of norepinephrine increased triglyceride and phospholipid level in
normally fed and cholesterol-fed rabbits, as well as total cholesterol level in
63
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cholesterol-fed rabbits.(104) Troxler et al demonstrated that plasma cortisol
levels were positively related to cholesterol and blood pressure leve!s.(105)
Larsson et al showed that platelet aggregability in vivo is enhanced by mental
stress and high physiological levels of circulating adrenaline.(106)
Accordingly, whether mediated by traditional risk factors or through alternative
mechanisms, sufficient evidence exsits to support the view that prolonged or
repetitive ANS arousal may induce injury to the blood vessels, hence, play a
part in intimal media thickening and later development of atherosclerosis.(45)
The assessment of cardiac reactivity recovery during a resting process
is a novel approach. In this report, we considered the 15-30 minutes of
ultrasound examination to be a resting process. We must recognize,
however, that this was not a standardized protocol designed to produce
reliable cardiac reactivity measures. The correlation between Exam 1 and
Exam 3 for change in SBP was 0.10 (p=0.03), for change in DBP was 0.09
(p=0.04), for change in heart rate was 0.06 (p=0.19). Considering that out
detected associations would be attenuated if measurement of the reactivity
variables were measured with error, more reproducible and precise
measurements might reveal stronger associations with IMT.
The data seems to generate contradiction findings: while less decrease
in DBP and HR were correlated with thicker IMT, those whose SBP dropped
the most was more prone to LDL-C related atherosclerosis. These results
64
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may indicate that cardiovascular reactivity and high SBP might be two
independent risk factors in early atherosclerosis. On the one hand, less SBP
drop, together with less DBP drop and HR drop, indicates less cardiac
recovery during a resting period, which may be correlated with thicker IMT.
On the other hand, if with the same average SBP, less SBP drop means lower
absolute SBP levels, which may result in less injury on artery walls, and less
LDL-C reduced IMT increase.
Besides elevated average SBP and before resting SBP may promote
LDL-C induced wall thickening, current cigarette smoking may also increase
the dependency of IMT on LDL-C. The results from different samples and
from both cross-sectional and longitudinal analysis show a consistent positive
relationship between serum LDL-C and CCA IMT only in currently smoking
women, but not in women who were former- or non-smokers. This finding
does not seem to hold in men, although IMT is thickened in currently smoking
men.
While cigarette smoking and progression of atherosclerosis were
detected from a large study of 10,914 participants and a follow-up duration of
3 years,(72) 4 smaller studies yielded mixed results. In 100 Finnish men, a
significant positive association was found between pack-year smoking and 2
year change in IMT.(68) Smoking was shown to be related to annual IMT
progression rate in MARS.(108) However, 2 other studies did not yield
65
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significant relationship between smoking status and atherosclerosis
progression.(39, 109) In some trials of LDL-C lowering and IMT
progression/regression in 424 men, larger treatment effects were found in
smokers.(108, 110)
How exactly cigarette smoking modulates the dependency of LDL-
induced early atherogenesis among women is not clear. It might be through
the initial stage-setting of wall injury;(73) it might also be mediated by change
in LDL-C, HDL-C, and other lipids moderation.(85-87) The other possible
pathway that might partly explain the gender difference in our findings were
the effects of smoking on increased levels of catecholamine.(81, 82) Smoking
were shown to be associated with a marked and prolonged increase in
plasma norepinephrine and epinephrine.(111-113) With a- and |3- adrenergic
blockade, the smoking induced hemodynamic changes are markedly
attenuated.(111, 114-116) These findings prompted the hypothesis that the
mechanism responsible for the pressor and tachycardic responses of smoking
may have an adrenergic nature. In the ‘Los Angeles Atherosclerosis Study’,
smoking, especially cumulative pack-years of smoking, is related with pulse
pressure in women, but not in men.
It is interesting to note that in the ‘Los Angeles Atherosclerosis Study’,
current smoking status is positively related with IMT in men, but not in women,
however, both cross-sectional and longitudinal data show that current
66
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smoking promote LDL-C induced wall thickening in women, but not in men.
One possible explanation is a greater protection of women against arterial
injury from factors other than blood pressure in this age group. Because of
less protection, men’s smoking may be much faster than women’s smoking to
render detrimental effects on injuring artery wall. The smoking generated
injury in men might be so severe that LDL-C penetration into the artery wall
from low LDL-C serum level is enough to thicken the artery wall quickly. So,
in this age group, only a smoking thickened IMT, but not a smoking modulated
relationship between IMT/AIMT and LDL-C, was found in men smokers. On
the contrary, because of more protection, smoking generating wall injury and
LDL-C penetration into the artery wall are still an on-going process in women.
So, only a smoking modulated relationship between IMT/AIMT and LDL-C,
but not a smoking thickened IMT, was found in women smokers. A indirect
check of this hypothesis is the difference in prevalence of lesion in women
and men. As depicted in Figure 18, while not adjusting for smoking status, the
odds of having at least one lesion in left or right carotid artery in men is
significantly higher than in women (OR=2.51, 95%CI: 1.15-5.52, p=0.02).
Adjusted for smoking status, the between sex difference is less significant
(OR=2.17, p=0.06).
67
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Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Figure 18: Prevalence of Lesion, By Sex
o
• H
C/D
O
cO
60
C G
w
o
( A
TJ
T )
O
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
- Women ■ Men
1 1
i 1
Model 1 statistical Model Model 2
Model 1: adjusted for age, sex, body height, race, body mass index, SBP, diabetes,
medication status for hypertension and hypercholesterolemia.
Model 2: adjusted for all in model 1, and smoking status
O )
c o
Figure 19 to summarizes the findings in this dissertation study. It is
postulated that elevated systolic blood pressure, larger drop in SBP during a
cardiovascular recovery by a resting process, and current cigarette smoking
are all independent risk factors in early atherosclerosis which will yield arterial
wall injury. The arterial wall injury will then set the stage for further LDL-L
induced atherosclerosis. Less decrease in DBP and HR in cardiovascular
recovery during a resting period might be an independent risk factor in early
atherosclerosis.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Figure 19: Artery Wall Injury, LDL-C, and Early Atherosclerosis, A
Postulated Pathway
AHR
CV Recovery ADBP
IMT/
AIMT
ASBP
/ Initial
* Wall
A Injury
Cigarette
Smoking
BP
Early
Atherosclerosis
LDL-C
o
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Artery wall injury and LDL-cholesterol in early atherosclerosis: The Los Angeles atherosclerosis study
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