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Comparative biomolecular and therapeutic effectiveness of collaborative integrative intervention in morbidly obese individuals

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Comparative biomolecular and therapeutic effectiveness of collaborative integrative intervention in morbidly obese individuals

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Content COMPARATIVE BIOMOLECULAR AND THERAPEUTIC
EFFECTIVENESS OF COLLABORATIVE INTEGRATIVE
INTERVENTION IN MORBIDLY OBESE INDIVIDUALS

by

Naser Ahmadi

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

May 2012

Copyright 2012 Naser Ahmadi
ii

EPIGRAPHS

“The future belongs to those who believe in the beauty of their dreams.”
– Eleanor Roosevelt

“Learn from yesterday, live for today, hope for tomorrow. The important thing is
not to stop questioning.”
– Albert Einstein
iii

DEDICATION

This thesis is dedicated to my father, who taught me that the best kind
of knowledge to have is that which is learned for its own sake. It is
also dedicated to my mother, who taught me that even the largest
task can be accomplished if it is done one step at a time. Finally, this
is dedicated to my wife, who inspired me with her passion and love
the ways of being better human being and realizing my dreams.

iv

ACKNOWLEDGEMENTS

Drs. Stanley Azen, Wendy Mack and Howard Hodis have been the
ideal thesis supervisor, and academic role models. Their sage advice,
insightful criticisms, and patient encouragement aided the writing of
this thesis in innumerable ways. I would also like to thank sincerely Mr
Roland Rapanot whose steadfast support of this project was greatly
needed and deeply appreciated.

v

TABLE OF CONTENTS

Epigraph ii
Dedication iii
Acknowledgements iv
List of Tables vii
List of Figures viii
Abstract ix
Introduction: Obesity and Atherosclerosis
Prevalence of Obesity.
Risk Factors for Obesity.
Oxidative Stress biomarkers and Obesity.
Vascular Dysfunction and Obesity.
Adipose Tissue Assessment and Obesity.
Obesity and treatment guidelines.
Obesity, Treatment and Change in Weight and Fat Mass.
Obesity, Treatments and Side Effects.
Obesity and Gene Expression
1
1
2
2
3
3
4
5
6
7
Chapter One: Knowledge Gap in Obesity Management and Our
Proposal
Background and Knowledge Gap:
SPECIFIC AIMS

8

8
10
Chapter Two: Collaborative Intervention Research Plan:
Importance and Rationale
RESEARCH PLAN
– Significance
– Impact
– Innovation
– Rationale
12

12
16
16
19
vi

PRELIMINARY FINDINGS:
- The roles of direct measures of atherosclerosis vs.
traditional risk stratification in Obesity.
- Oxidative Biomarkers, Adipose Tissue and Coronary
Artery Calcium.
- Metabollically Active Adipose Tissue and Response to
therapy.
- Obesity and Intense Exercise and Caloric Restriction.
21
21

21

24

25
Chapter Three: Collaborative Intervention Research Plan:
Approach
Approach.
Synopsis.
Procedures
Interventions.
Data Collection and Management.
Specific Aim 1)
SA1) Sample size estimation.
SA1) Statistical Analysis.
Specific Aim 2)
SA2) Sample size and power.
SA2) Statistical Analysis.
Specific Aim 3)
SA3) Sample size and power.
SA3) Statistical Analysis.
29

29
31
33
39
43
44
44
46
48
48
48
50
51
52
Chapter Four: Study Timelines, Ethics and Environment
Timeline
Ethical aspects of the proposed research
Environment
Study administration and personnel
54
55
55
56
56
Conclusion 58
Bibliography 59

vii

LIST OF TABLES

TABLE 1 Demographics of Subject Receiving Garlic Extract 23
TABLE 2 Relation of Garlic Therapy and Decrease in
Atherosclerosis
24
TABLE 3 Demographics of Intense Exercise- Moderate
Calorie Restriction
26
TABLE 4 Association of Changes in Inflammatory Biomarkers,
Insulin Sensitivity with Improvement in Carotid Artery
Distensibility
27
TABLE 5 Biochemical Variables Associated with
Changes in Carotid Artery Distensibility
27
TABLE 6 Procedure Tables 33
TABLE 7 Power Calculation based on Change in
Carotid IMT
44
TABLE 8 Power Calculation based on Change in Fat
Mass
45
TABLE 9 Power Calculation based on Change in TNFRII 45

viii

LIST OF FIGURES

FIGURE 1 Fat Distribution of Two Individuals with Similar Weight 6
FIGURE 2 Knowledge Gap and Solution 20
FIGURE 3 Decrease in carotid intima media thickness with increase
in lipoprotein (a) and adiponectin, and decreases in
insulin resistance and inflammation during the 7-month
intense exercise and diet program
27
FIGURE 4 Collaborative Integrative Interventions
30
FIGURE 5 Eligibility Criteria 32
FIGURE 6 Study Protocol Scheme 33
FIGURE 7 Carotid Intima Media Thickness 34
FIGURE 8 Mixed Carotid Plaque 34
FIGURE 9 Coronary Artery Distensibility Index 36
FIGURE 10 Motivational Interviewing 40
FIGURE 11 Mechanistic Models to Develop Individualized
Intervention
51

ix

ABSTRACT

Background. Obesity is prevalent and linked with inflammation, insulin
resistance, dyslipidemia, atherosclerosis, and associated with significant
morbidity and mortality. The economic burden of obesity-related illnesses is
substantial, with estimates ranging from 2% to 7% of the total US health care
expenditures and billions of dollars in direct and indirect costs to society. This
goal will be accomplished by collaborative integrative interventions (CI) in
morbidly obese individuals in which eligible subjects will be randomized to MI
plus Gastric bypass surgery (GBS), intense exercise and moderate caloric
restriction (IE-MCR), or anti-obesity medications (AOM).
Importance/Significance. There is a cumulative increase in the rate of obesity,
up to two thirds of the US population. This randomized clinical trial will assess: 1)
the change in biologic and clinical phenotypes in response to CI, 2) the change in
genotypes in response to CI, and 3) Comparative biomolecular, therapeutic and
cost effectiveness analyses of methods of CI to develop individualized
intervention models to improve management of morbidly obese individuals.
vascular function measured as coronary distensibility index (CDI), atherosclerotic
burden measured as carotid intima media thickness (CIMT) and coronary plaque
x

volume (CPV), metabolically active adipose tissue (MAC), oxidative stress and
inflammatory biomarkers se well as changes in DNA methylation patterns,
expression and regulation of promoter regions of genes provides fundamental
information to assess the beneficial effects within and across CI methods on
obesity management. This study investigates the underlying determinant of
successful management of obesity by comparing biologic, clinical phenotype,
genotype and cost effectiveness of CI methods, also enhances individualized
anti-obesity interventions.
Method. The CI methods are hypothesized to improve CDI and reduce CIMT,
CPV and MAC, also increase up-regulation of cardio-protective genes. Over a 3
year period, 150 morbidly obese individuals’ ages 18 or older and free of clinical
cardiovascular disease will be recruited from the Obesity Clinic of the Greater
Los Angeles VA Health Care System, University of California Los Angeles and
Cedars Sinai Medical Center. One hundred and fifty eligible subjects will be
randomized to either of CI methods inclusive of MI plus GBS, IE-MCR, or AOM
(50 in each group). All subjects will receive weekly MI training for a year. MI plus
IE-MCR will receive lectures on exercise and general dietary measures including
calorie counting. They will prepare their own food, with protien:carbohydrate:fat
ratio of 30:45:25 and over 70% their resting daily energy expenditure, and
completed daily food and exercise journals. They will exercise 3 ± 2 hours/day,
about half supervised, for a year. MI plus GBS will undergo primary laparoscopic
RYGB. MI plus AOB will receive xx pills daily for a period of 1-year. All subjects
xi

will be followed before, during and after interventions. Subjects will undergo
carotid ultrasound and CT at baseline and at 1-year follow-up, also their oxidative
stress and inflammatory biomarkers as well as genetic markers will be assessed.
CI methods’ compliance and side effects will be evaluated.
1

INTRODUCTION: OBESITY AND ATHEROSCLEROSIS

Prevalence Of Obesity.
Obesity is a chronic condition that is associated with significant morbidity and
mortality(Flegal, Carroll, Ogden, & Curtin, 2010). In addition to increased total
mortality, obesity is associated with a number of chronic conditions including
inflammation, insulin resistance, atherosclerosis, stroke, type 2 diabetes, heart
failure, dyslipidemia, hypertension, and sleep apnea.(Kenchaiah et al., 2002;
Williamson & Pamuk, 1993) Cardiovascular death has been reduced significantly
because of improvements in detection and management of coronary artery
disease (CAD) over the past few decades.(Flegal, Carroll, Ogden, & Johnson,
2002; Fox, Evans, Larson, Kannel, & Levy, 2004; Hu et al., 2000; Thom et al.,
2006) However the recent increase in the rate of overweight and obesity, up to
two thirds of the US population in both sexes across age groups, may diminish
the favorable effect of recent improvements in the diagnosis and treatment of
CAD.(Agatston et al., 1990; Flegal, Carroll, Kuczmarski, & Johnson, 1998; Flegal
et al., 2002; Hu et al., 2000; Ogden et al., 2006; Wheeler et al., 2005) Obesity is
a modifiable risk factor for atherosclerotic CAD, and current American College of
Physician (ACP) guidelines recommend non-pharmacological, pharmacological
and surgical interventions to treat obesity and its associated complications.(Lau
et al., 2007; R. S. Padwal & Majumdar, 2007)
2

Risk Factors For Obesity.
Adipocytes secrete numerous factors that could potentially modulate the
development of vascular disease, including pro-inflammatory cytokines and
adipokines, angiogenic molecules, and stem cell homing factors.(Jeong et al.,
2007; Maurovich-Horvat et al., 2007) Earlier evidence indicates that adipose
tissue is a functional component, exerting paracrine influences on blood vessel
contractility.(Lohn et al., 2002) Expansion and uncontrolled remodeling of
adipose tissue is associated with increased inflammation, insulin resistance,
dyslipidemia, obesity, cardiovascular risk factors, metabolic dysfunction, and
CAD. Obesity is associated with multiple markers of inflammation, vascular
dysfunction and oxidative stress, including C-Reactive Protein (CRP), fibrinogen,
intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant
protein-1 (MCP-1), P-selectin, tumor necrosis factor receptor-2, and urinary
isoprostanes, vascular endothelial growth factor, and plasminogen activator
inhibitor-1.(Bruun, Lihn, Pedersen, & Richelsen, 2005; Tadros et al., 2009)
Increased levels of chemokine MCP-1 in adipose tissue attract more T
cells/monocytes/macrophages, inducing a self-sustaining inflammatory
cycle.(Curat et al., 2006; Suganami, Nishida, & Ogawa, 2005) Furthermore,
obesity is independently associated with coronary artery disease, and an adverse
outcome.(Hofso et al., 2010)

3

Oxidative Stress Biomarkers And Obesity.
Increases in plasma levels of Lipoprotein (a), The content of oxidized
phospholipids (OxPL) on apolipoprotein B-100 (apoB) particles detected by
antibody E06 (OxPL/apoB), and adiponectin, have been associated with
evidence of the concomitant removal of OxPL from the vessel wall and plaque
stabilization with statin therapy and low fat diet in animal studies.(Ben Ounis et
al., 2009; Fraley et al., 2009; Rokling-Andersen et al., 2007) Increases in
OxPL/apoB and Lp(a) strongly correlated with increases in vascular function and
predict lack of progression of atherosclerosis after aged garlic extract and
supplement and non-pharmacological obesity intervention(Ahmadi N, Eshaghian
S, et al., 2010; Ahmadi, Tsimikas, et al., 2010a) . Increases in Lp(a) after a low
fat high carbohydrate diet are positively correlated with changes in medium size
LDL particles, suggesting that the metabolism of Lp(a) and medium LDL may be
coordinately regulated. In human epidemiological studies, this relationship is less
consistent and more complex, in general showing that these markers are
univariate predictors of various manifestations of cardiovascular disease but not
always independently predictor(s) of cardiovascular events.

Vascular Dysfunction And Obesity.
Vascular dysfunction is associated with higher risk of subsequent
atherosclerotic cardiovascular events.(Yeboah, Crouse, Hsu, Burke, &
Herrington, 2007) Strong correlations also exist between vascular dysfunction
and cardiovascular risk factors, obesity and atherosclerosis.(Kirma et al., 2007)
4

Nevertheless, there is considerable heterogeneity in the magnitude of vascular
dysfunction in individuals with similar risk profiles.(Halcox et al., 2002) In this
regard, vascular dysfunction may be seen as an important "integrative factor" for
atherosclerosis in individuals.(Halcox et al., 2002). In addition to risk assessment
for prediction of clinical outcomes, measures of vascular function may also be
used to evaluate response to therapies.(Binggeli et al., 2003; Minson & Wong,
2004)

Adipose Tissue Assessment And Obesity.
Anthropometric measures such as body mass index (BMI) or waist
circumference have traditionally been used to estimate overall adiposity.
However, direct measures of region-specific adipose tissue are superior to
estimated overall adiposity for the identification and management of high-risk
individuals.(Flegal et al., 2002; Hamdy, Porramatikul, & Al-Ozairi, 2006; Hu et al.,
2000; Ogden et al., 2006) Recent studies have revealed a significant
independent association on increase in adipose tissue with the presence and
severity of coronary atherosclerosis after adjustment for conventional risk factors
and BMI.(Ahmadi, Nabavi, et al., 2010) This highlights the importance of
localized and systemic effect of adipose tissues, independent of BMI, in the
subclinical burden of atherosclerosis.

Obesity And Treatment Guidelines.
Guidelines for the prevention of CAD advocate the assessment of risk based
on multiple risk factors, and recognize the contributions of non-modifiable (age,
5

gender, family history of CHD) and modifiable (smoking, dyslipidemia,
hypertension, obesity, glucose resistance/diabetes) factors(R. Padwal, Li, & Lau,
2003). In recent years, awareness of the contribution of obesity and metabolic
syndrome to CAD has increased. The latest revision of the US guidelines
recognizes that excess body fat, particularly visceral adiposity, promotes the
development of insulin resistance and metabolic syndrome. Moreover, obesity
has been identified as a criterion for metabolic syndrome and treatment of this
condition is specified as a secondary target of therapy.(Genest et al., 2009; R.
Padwal et al., 2003) The guidelines also highlight the importance of reducing the
underlying causes of the metabolic syndrome, identified as obesity and physical
inactivity. However, none of the guidelines include obesity as a factor in the
assessment and management of CAD risk.(Eckel et al., 2004; Flegal et al., 2010;
R. Padwal et al., 2003)

Obesity, Treatment and Change In Weight And Fat Mass.
Surgical, pharmacological and non-pharmacological obesity treatments result
in clinically significant weight loss and favorable changes in cardio-metabolic risk
factors. (Figure 1) However, there are significant differences between above
mentioned treatments in fat mass reduction.(Genest et al., 2009; Rucker,
Padwal, Li, Curioni, & Lau, 2007) Fat Mass reduction was substantially greater in
12-month gastric bypass surgery follow-up than individuals who underwent 12-

6

month moderate self-
monitored physical activity
and diet (-32.7% vs. -10%),
however, gastric bypass
surgery was associated with
less fat mass reduction as
compared to intense exercise
and diet program (-47.6% vs. -
32.7%).

(Ahmadi N,
Eshaghian S, et al., 2010; Hofso et al., 2010; Madan, Kuykendall, Orth,
Ternovits, & Tichansky, 2006; Strain et al., 2009; Zalesin et al., 2010)

Obesity, Treatments And Side Effects.
Considerable advances have been made in dietary, exercise, behavioral,
pharmacologic and bariatric surgical approaches to successful long-term
management of obesity. Lifestyle interventions remain the cornerstone of the
treatment of obesity, but adherence is poor and long-term success is modest
because of significant barriers both on the part of affected individuals and health
care professionals responsible for the treatment.(Genest et al., 2009; Lau et al.,
2007; R. S. Padwal & Majumdar, 2007) Pharmacotherapy and bariatric surgery
are useful adjuncts for improving the health outcomes of overweight people, but,
for a variety of reasons including considerable side effect profiles and financial
Figure 1 Fat Distribution of Two Individuals with Similar Weight
7

expense(Abenhaim et al., 1996; Luque & Rey, 1999), these modalities of
treatment are not widely adopted. Surgical procedures such as gastric bypass
have the greatest long-term success rates (approximately 20% weight loss after
ten years) but are currently indicated only for the morbidly obese(Sjostrom et al.,
2004). In addition, these procedures are associated with significant cost, long-
term complications and mortality.(Greenway, 1996)

Obesity And Gene Expression.
Adipose tissue lipid storage and processing capacity can be a key factor for
obesity-related metabolic disorders such as insulin resistance and diabetes. Lipid
uptake is the first step to adipose tissue lipid storage. Recent study studied the
gene expression of factors involved in lipid uptake and processing in
subcutaneous (SAT) and visceral (VAT) adipose tissue according to body mass
index (BMI) and the degree of insulin resistance (IR). It suggests that morbidly
obese patients have a lower gene expression of factors related with lipid uptake
and processing including lipoprotein lipase (LPL), acylation stimulating protein
(ASP), LDL receptor-related protein 1 (LRP1) and fatty acid binding protein 4
(FABP4), in comparison with healthy lean persons.(Clemente-Postigo et al.,
2011)

8

CHAPTER ONE: KNOWLEDGE GAP IN OBESITY
MANAGEMENT AND OUR PROPOSAL

Background And Knowledge Gap.
Obesity is linked with inflammation, insulin resistance, dyslipidemia,
atherosclerosis(Kenchaiah et al., 2002; Williamson & Pamuk, 1993) and
associated with significant morbidity and mortality(Flegal et al., 2010). There is a
cumulative increase in the rate of obesity, up to two thirds of the US population.
This major public health problem may diminish the favorable effect of recent
improvements in the diagnosis and treatment of coronary artery disease (CAD).
There is also significant psychosocial stigma associated with being obese. (Bray,
1998) The economic burden of obesity-related illnesses is substantial, with
estimates ranging from 2% to 7% of the total US health care expenditures and
billions of dollars in direct and indirect costs to society.(Birmingham, Muller,
Palepu, Spinelli, & Anis, 1999; Seidell, 1995) Anti-obesity medications (AOM)
have a modest beneficial effect on reducing CAD risk.(Abenhaim et al., 1996;
Luque & Rey, 1999) Gastric bypass surgery (GBS) has the greatest long-term
success rates, but is indicated only for the morbidly obese
individuals.(Greenway, 1996; Sjostrom et al., 2004) Intense exercise and
moderate caloric restriction (IE-MCR) is associated with improvement in carotid
vascular function and atherosclerosis as well as a reduction in inflammatory
9

biomarkers in morbidly obese individuals. Motivational interviewing (MI) offers a
promising supplementary component of obesity-management and was found to
be feasible to implement.(Carels et al., 2007; Flattum, Friend, Neumark-Sztainer,
& Story, 2009) While different treatments have been adopted for the obesity
management, there is a significant and critical need for comparative biomolecular
and therapeutic effectiveness research of such interventions to understand
underlying biologic, phenotype and genotype mechanisms in response to these
interventions. Since most morbidly obese individuals suffer both psychological
and medical complications of obesity, comprehensive interventions to address
both are needed. This goal will be accomplished by collaborative integrative
interventions (CI) in morbidly obese individuals in which eligible subjects will be
randomized to MI plus GBS, IE-MCR, or AOM. Changes in vascular function
measured as coronary distensibility index (CDI), atherosclerotic burden
measured as carotid intima media thickness (CIMT) and coronary plaque volume
(CPV), metabolically active adipose tissue (MAC), oxidative stress and
inflammatory biomarkers se well as changes in DNA methylation patterns,
expression and regulation of promoter regions of genes in response to CI, will be
evaluated. The overall goal of this study is to investigate: 1) the change in
biologic and clinical phenotypes in response to CI, 2) the change in genotypes in
response to CI, and 3) Comparative biomolecular, therapeutic and cost
effectiveness analyses of methods of CI to develop individualized intervention
models to improve management of morbidly obese individuals.
10

The Biggest Loser Study (BLS): In Feb 2005, we initiated a prospective
community-based IE-MCR intervention, with the goal of identifying novel
mechanisms for obesity management. Over the past years we have completed
over 17 series of IE-MCR successfully and developed skilled team and advanced
protocols in this regard. In addition, we have been working closely with surgery
department and obesity center of University of California Los Angeles to study
GBS and AOM subjects. Utilizing these growing resources, we propose to
develop a comparative effectiveness research for development of individualized
intervention for morbidly obese individuals.

Specific Aims.
1) To evaluate the change in CDI, CIMT, CPV, MAC, oxidative stress and
inflammatory biomarkers in response to CI, Based on the hypothesis that obesity
management will be significantly enhanced by incorporating intervention biologic
and clinical phenotype mediators identified in each CI component, we propose:
1a) To assess of the change in CIMT measured by ultrasound, and CDI and CPV
measured by computed tomography (CT), 1b) to evaluate the change in MAC
and fat mass measured by CT, and 1c) To compare the change oxidative stress
and inflammatory biomarkers in response to CI within and across CI-methods.
2) To assess the change in DNA methylation patterns, expression and regulation
of promoter regions of genes, and their interaction with phenotypes in response
to CI, Based on the hypothesis that identification of genotype change in response
to CI and its interaction with phenotype will be significantly improve obesity
11

management, we propose: 2a) To evaluate the change in DNA methylation
patterns, expression and regulation of promoter regions of genes critically
involved in the endothelial function, cholesterol efflux, glucose metabolism,
atherosclerosis, and adipose tissue activity in response to CI within and across
CI-methods, 2b) assessment of interaction between change in genotype and
phenotype, and
3) Comparative biomolecular, therapeutic and cost effectiveness analyses of 3
methods of CI to develop individualized intervention models to improve
management of morbidly obese individuals. Based on the hypothesis that CI
method-specific changes in biologic, clinical phenotype and genotype will
significantly enhance individualized intervention models, we propose: 1) To
compare the biologic, clinical phenotype, and genotype effectiveness within and
across CI methods, 2) To compare cost effectiveness within and across CI
methods, to develop individualized intervention models to improve management
of morbidly obese individuals, and reduce future events.

12

CHAPTER TWO: COLLBORATIVE INTERVENTION
RESEARCH PLAN: IMPORTANCE AND RATIONALE

Research Plan.
Significance. Obesity is associated with significant morbidity and mortality(Flegal
et al., 2010). There is a cumulative increase in the rate of obesity, up to two
thirds of the US population. This major public health problem may diminish the
favorable effect of recent improvements in the diagnosis and treatment of
coronary artery disease (CAD). The economic burden of obesity-related illnesses
is substantial, with estimates ranging from 2% to 7% of the total US health care
expenditures and billions of dollars in direct and indirect costs to
society.(Birmingham et al., 1999; Seidell, 1995) Clearly, better understanding of
biologic mechanism of anti-obesity managements are needed to more
specifically identify biologic, phenotype and genotype changes in response to
different anti-obesity treatment. This can be successfully provided models to
develop individualized intervention for anti-obesity management.
A1) Importance: understanding fundamental aspects of biologic , phenotype and
genotype differences in response to different components of collaborative
integrative interventions. Adipocytes secrete numerous factors that could
potentially modulate the development of vascular disease, including pro-
inflammatory cytokines and adipokines, angiogenic molecules, and stem cell
13

homing factors.(Jeong et al., 2007; Maurovich-Horvat et al., 2007) Earlier
evidence indicates that adipose tissue is a functional component, exerting
paracrine influences on blood vessel contractility.(Lohn et al., 2002) Obesity is
associated with multiple markers of inflammation, vascular dysfunction and
oxidative stress, including CRP, fibrinogen, intracellular adhesion molecule-1,
interleukin-6, monocyte chemoattractant protein-1 (MCP-1), P-selectin, tumor
necrosis factor receptor-2, and urinary isoprostanes, vascular endothelial growth
factor, and plasminogen activator inhibitor-1.(Bruun et al., 2005; Tadros et al.,
2009) Increased levels of chemokine MCP-1 in adipose tissue attract more T
cells/monocytes/macrophages, inducing a self-sustaining inflammatory
cycle.(Curat et al., 2006; Suganami et al., 2005) Furthermore, recent studies
document that obesity is independently associated with coronary artery disease,
and an adverse outcome.(Hofso et al., 2010)
In addition, significant differences in mean weight loss and decrease in fat
mass with various anti-obesity interventions as well as large knowledge gap in
biologic, phenotype and genotype changes in response to non-pharmacological,
pharmacological, and surgical anti-obesity interventions have been reported.
(Ahmadi et al., 2009; Shaw, Bugiardini, & Merz, 2009) Functional integrity of the
endothelium has anti-atherosclerotic and antithrombotic implications, and
vascular dysfunction is an important integrative factor leading to the development
and burden of atherosclerosis, especially in obese individuals.(Kirma et al., 2007)
Oxidative stress impairs vascular function, and its interaction with vascular
14

dysfunction play a cumulative effect in the pathogenesis and progression of
atherosclerosis, especially in obese individuals. Increases in plasma levels of
Lipoprotein (a), OxPL/apoB, and adiponectin, have been associated with
evidence of the concomitant removal of OxPL from the vessel wall and plaque
stabilization with statin therapy and low fat diet in animal studies.(Ben Ounis et
al., 2009; Fraley et al., 2009; Rokling-Andersen et al., 2007) Anti-obesity
medications (AOM) have a modest beneficial effect on reducing CAD
risk.(Abenhaim et al., 1996; Luque & Rey, 1999) Gastric bypass surgery (GBS)
has the greatest long-term success rates, but is indicated only for the morbidly
obese individuals.(Greenway, 1996; Sjostrom et al., 2004) Intense exercise and
moderate caloric restriction (IE-MCR) is associated with improvement in carotid
vascular function and atherosclerosis as well as a reduction in inflammatory
biomarkers in morbidly obese individuals. Motivational interviewing (MI) offers a
promising supplementary component of obesity-management and was found to
be feasible to implement.(Carels et al., 2007; Flattum et al., 2009) While different
treatments have been adopted for the obesity management, the change of such
vascular dysfunction, atherosclerotic burden, inflammatory biomarkers and
pharmacogenomics following therapeutic interventions is not well studied. Since
most morbidly obese individuals suffer both psychological and medical
complications of obesity, comprehensive interventions to address both are
needed.
15

A2) Critical barriers: comparative biomolecular and therapeutic effectiveness
research to understand underlying biologic, phenotype and genotype
mechanisms in response to anti-obesity. Obesity is a multifactorial systemic
disease, associated with significant morbidity and mortality. This highlights the
necessity of comprehensive evaluation of biologic, phenotype and genotype
aspects of obesity in response to different therapies. The current anti-obesity
interventions, while useful, are based on the their effect on weight loss and/or fat
mass rather than underlying intervention-specific biologic, phenotype and
genotype mechanisms for pathogenesis / progression of functional and
anatomical atherosclerotic changes, inflammation, lipid metabolism and
biomolecular change in response to collaborative interventions. These
shortcomings result in: 1) mismanagement, and misclassification of responder
and non-responder to such interventions, 2) lack of proper monitoring rate of
disease progression both physical and psychological complications of obesity, 3)
significant residual risk despite optimal weight loss, and 4) lack of comprehensive
effective anti-obesity management strategy; resulting in a significant need to
conduction of collaborative integrative interventions to develop individualized
anti-obesity interventions.
A3) Improvement of scientific knowledge: understanding intervention-specific
mechanistic models for change in biology, phenotype and genotype to develop
individualized intervention for morbidly obesity management. This comparative
effectiveness research addresses critical aspects of comprehensive anti-obesity
16

management. Those include: 1) understanding the biologic and clinical
phenotype changes in response to CI, 2) pharmacogenomics changes in
response to CI, and 3) Comparative biomolecular, therapeutic and cost
effectiveness analyses of methods of CI to develop individualized intervention
models to improve management of morbidly obese individuals. Individualized
intervention models can reduce long term cardiovascular event risk of obesity by
improving atherosclerosis management, monitoring response to therapies; based
on biologic, phenotype and genotypes. We will investigate the role of each CI
component on vascular function, oxidative stress, cholesterol efflux, vascular wall
and stabilize plaques, to identify proper management of vulnerable morbidly
obese individuals.

Impact.
This comparative effectiveness research will be a comprehensive anti-obesity
interventional approach, allowing patients and providers to adopt appropriate
individualized anti-obesity intervention as well as response monitoring approach
who would benefit patients’ the most; with significant implications for current cost
of health care as well as overall public health. If successful, this proposal will be
available for large scale studies following which it could potentially be deployed in
daily clinical practice.

17

Innovation.
This prospective randomized clinical trial will compare biologic, clinical
phenotypes and genotypes effectiveness of collaborative integrative intervention
and its components on proper management of morbidly obesity. This is an
unusually comprehensive anti-obesity interventions model, and to our
knowledge, this will be the first, for understanding and developing novel
individualized intervention models to reduce cardiovascular atherosclerotic
burden and inflammation, improve vascular function and detect intervention-
specific pharmacogenomics. The large gap in decrease in weight and lack of
optimal reduction in atherosclerosis and inflammation following anti-obesity
interventions remains significant. The focus of study is to investigate the
underlying causes of such differences, and develop model to address these
major public health problem. Comprehensive and simultaneous assessment of
vascular function measured as carotid (CaDI) and coronary (CDI), atherosclerotic
burden measured as carotid intima media thickness (CIMT) and coronary plaque
volume (CPV), metabolically active adipose tissue (MAC), oxidative stress and
inflammatory biomarkers se well as changes in DNA methylation patterns,
expression and regulation of promoter regions of genes provides fundamental
information to assess the beneficial effects within and across CI methods on
obesity management. Finally, mechanistic models for biologic, clinical and
pharmacogenomics changes in response to components of CI will be developed
using advanced statistical analysis. Furthermore, comparative therapeutic and
cost effectiveness of such CI components will be employed. The team presenting
18

this proposal are the only ones working with anti-obesity interventions in a such
detail, and we have been able to explain many aspects of the process, from the
evolutionary processes allowing: a) identification of novel mechanism of IE-MCR
intervention on obesity management, b) development and validation of novel
non-invasive methods to assess vascular function, plaque buildup, composition
and vulnerability, and metabolically active adipose tissue, and c) develop and
validate advance statistical analyses for comparative effectiveness research,
pattern recognition, novel atherosclerosis marker discovery and exploratory
models, monitoring response to the therapies, and genotype phenotype
interactions. There are several fundamental issues being investigated in these
studies, including being able to obtain a detailed understanding of underlying
mechanism of change in biologic, clinical phenotypes and genotype in response
to CI components, and conducting comparative biomolecular, therapeutic and
cost effectiveness analyses of methods of CI to develop individualized
intervention models to improve management of morbidly obese individuals. We
use a variety of advanced novel anti-obesity interventional protocols including
intense exercise- moderate calorie restriction, gastric bypass surgery and anti-
obesity medication, plus motivational interviewing. Furthermore, we will use novel
non-invasive measures to assess vascular function, atherosclerotic burden,
inflammation and pharmacogenomics, also will employ computationally intensive
statistical analyses and advanced epidemiologic methods in these studies. While
some of the methods we propose are being used in preventive cardiology studies
19

(including by our laboratories) and some are developed/validated by us, the
proposed studies include combinations of those methods that are being used in
novel ways to gain a complete understating of the comparative biologic,
therapeutic and cost effectiveness of components of CI on appropriate obesity
management. Collaborative integrative intervention inclusive of psychological
and medical management of obesity, will inform the health care provider and
obese individuals the appropriate individualized anti-obesity intervention. If the
goals of the proposed project can be accomplished, there are significant
implications for individualized medicine to manage obesity. Therefore, this 5-year
proposal is aligned with the NHLBI mission to improve prevention and
management of obesity.

Rationale.
There is a cumulative increase in the rate of obesity, up to two thirds of the US
population. There is significant psychosocial stigma associated with being
obese.(Bray, 1998) Furthermore, the economic burden of obesity-related
illnesses is substantial, with estimates ranging from 2% to 7% of the total US
health care expenditures and billions of dollars in direct and indirect costs to
society.(Birmingham et al., 1999; Seidell, 1995) While various non-
pharmacological, pharmacological, and surgical interventions to treat obesity, as
a critical and major public health problem, have been investigated, significant
residual cardiovascular risk, and side-effect profile remains. This warrants a
comparative biomolecular and therapeutic effectiveness research of such
20

interventions to understand underlying biologic, phenotype and genotype
mechanisms in response to these interventions. We hypothesize that
component-specific collaborative integrative intervention would significantly
enhance the management and monitoring response to therapy in morbidly obese
individuals - as compared to standard of care alone. Individualized anti-obesity
intervention is also likely to have a positive impact on the health care economics
of obesity prevention and management. Figure 2 illustrates the need for
collaborative integrative intervention for obesity and implications for patients if the
proposed project is successful.

The goal of this proposal is 1) the change in biologic and clinical phenotypes in
response to CI, 2) the change in genotypes in response to CI, and 3)
Figure 2 Knowledge Gap and Solution
21

Comparative biomolecular, therapeutic and cost effectiveness analyses of
methods of CI to develop individualized intervention models to improve
management of morbidly obese individuals. This proposal compares biologic,
therapeutic and cost-effectiveness of anti-obesity intervention, allows us to
extend beyond tradition markers of response to obesity such as weight and fat
mass. This makes a significant contribution to understand the beneficial effect of
psychological and medical anti-obesity intervention, and if the proposed project
achieves the outlined goals, there is potential for a significant contribution to this
major public health issue.

Preliminary Findings.
1) The Roles Of Direct Measures Of Atherosclerosis VS. Traditional Risk
Stratification In Obesity.
Recent studies have shown a significant proportion of patients categorized as
low to intermediate risk by the Framingham risk score (FRS), especially in
women, have significant coronary atherosclerosis. (Achenbach et al., 2003;
Ahmadi, Hajsadeghi, et al., 2011; Akosah, Schaper, Cogbill, & Schoenfeld, 2003;
Khot et al., 2003; Taylor et al., 2005; Vliegenthart et al., 2005) Furthermore,
cumulative evidence has pointed to the superior prognostic value of detecting
atherosclerosis measured by the presence and extent of atherosclerotic burden
rather than risk factor assessment by FRS to identify and manage at-risk
subjects for CAD.(Arad, Goodman, Roth, Newstein, & Guerci, 2005; Budoff et al.,
2009) Addition of atherosclerosis tests to the FRS significantly improves the
22

identification and prognostication of patients without CAD, especially in
individuals with obesity.

2) Oxidative Biomarkers, Adipose Tissue And Coronary Artery Calcium.
Oxidized low-density lipoprotein is primarily present in the vessel wall and has
pro-atherogenic and pro-inflammatory properties.(Glass & Witztum, 2001)
Oxidized LDL impairs vascular function and plays an important role in the
pathogenesis of atherosclerosis and is associated with various CAD
manifestations. Significant heterogeneity of lipid metabolism, insulin sensitivity,
balance of proinflammatory and anti-inflammatory biomarkers are reported on the
basis of anatomic locations.(Ahmadi, Tsimikas, et al., 2010b; Farley, Bast, &
Birrer, 2006; Kiechl et al., 2007; Steinberg, Parthasarathy, Carew, Khoo, &
Witztum, 1989; Tsimikas et al., 2006) We recently evaluated the effects of aged
garlic extract plus supplement (AGE+S) on adipose tissue, oxidative stress and
coronary artery calcium (CAC), and epicardial adipose tissue (EAT)
measurement at baseline and 12-month.(Ahmadi N, Zeb I, et al., 2010) The
content of oxidized phospholipids (OxPL) on apolipoprotein B-100 (apoB)
particles detected by antibody E06 (OxPL/apoB), lipoprotein(a), IgG and IgM
autoantibodies to malondialdehyde–low-density lipoprotein and apoB-immune
complexes were measured at baseline and after 12-month of treatment. From
baseline to 12 months, a strong correlation was noted between increase in EAT
and CAC (r
2
=0.54, p=0.0001). The increase in EAT correlated inversely with
increases in OxPL/apoB (r
2
= -0.66), and lipoprotein (a) (r
2
=-0.57) levels, but
23

positively with IgM (r
2
= 0.90) and IgG (r
2
= 0.57) autoantibodies to
malondialdehyde–low-density lipoprotein and apoB-immune complexes (p
<0.001 for all). At 1-year, the risks of CAC progression, increased EAT, and IgG
and IgM autoantibodies to MDA LDL and apoB-immune complexes were
significantly lower in AGE-S to placebo (p<0.05). (Table 1-2) Maximum beneficial
effect of AGE+S was noted with increase in OxPL/apoB and lipoprotein(a),
decrease in IgG and IgM malondialdehyde–low-density lipoprotein, and lack of
progression of EAT and CAC. Increases in OxPL/apoB and lipoprotein (a)
correlated strongly with decreases in EAT and predicted a lack of progression of
CAC. (Ahmadi N, Zeb I, et al., 2010)

Variable AGE+S Placebo P
Baseline
CAC (AJ) 291±50 347±67 0.3
EAT (cc) 118±30 110±20 0.6
Lp(a), mg/dl 13.2±10.7 20.2±19 0.1
OxPL/apoB, RLU 4139±913 3231±719 0.4
IgG MDA-LDL, RLU 4054±353 3745±271 0.8
IgM MDA-LDL, RLU 2004±206 1800±234 0.3
IgG IC/apoB, RLU 4840±530 4668±392 0.5
IgM IC/apoB, RLU 2553±306 2101±258 0.5
Absolute Change in 1-year follow up
CAC (AJ) 22±18 62±43 0.005
EAT (cc) 11±8 21±7 0.01
Lp(a), mg/dl 23.6±9.8 25.6±14 0.001
OxPL/apoB, RLU 6397±522 4419±315 0.001
IgG MDA-LDL, RLU 2544±635 3650±410 0.001
IgM MDA-LDL, RLU 1116±2845 2264±117 0.008
IgG IC/apoB, RLU 2179±726 4551±663 0.001
IgM IC/apoB, RLU 1845±358 1856±389 0.001
Table 1 Demographics of Subject Receiving Garlic Extract
24

3) Metabolically Active Adipose Tissue And Response To Aged Garlic
Extract With Supplement Therapy.
We recently reported that computed tomography (CT) can accurately assess
metabolically active brown adipose tissue. In this trial, the effects of AGE-S on
metabolically active epicardial adipose tissue (mEAT), inflammation and CAC
among 60 asymptomatic subjects, randomized to AGE-S vs. placebo.
Participants underwent CT at baseline and 12-month, and their CAC, mEAT and
inflammatory biomarkers were measurement. From baseline to 12 months,
mEAT reduced in AGE-S as compared to placebo (-1.58±1.56 vs. 1.98±2.48,
p=0.003). Similarly, CAC progression, IgG and IgM autoantibodies to MDA LDL
and apoB-immune complexes were significantly lower in AGE-S to placebo
Model Placebo Aged Garlic
Extract OR(95%
CI)
P
CAC progression
†
1.0 (Ref) 0.35 (0.1 - 0.85) 0.03
Increased in EAT
∆
1.0 (Ref) 0.63 (0.43 – 0.90) 0.02
Increased in Lp(a)
∆
1.0 (Ref) 1.78 (1.1-2.2) 0.02
Increased in OxPL/apoB
∆
1.0 (Ref) 1.30 (1.1-1.8) 0.01
Increased in IgG MDA-LDL
∆
1.0 (Ref) 0.74 (0.16-0.87) 0.02
Increased in IgM MDA-LDL
∆
1.0 (Ref) 0.80 (0.1-0.9) 0.02
Increased in IgG IC/apoB
∆
1.0 (Ref) 0.82 (0.05-0.9) 0.03
Increased in IgM IC/apoB
∆
1.0 (Ref) 0.78 (0.1-0.9) 0.02
Logistic regression Analysis
Adjusted for age, gender, diabetes mellitus, Hypertension,
Hyperlipidemia, Family History of CHD, Smoking status, Statin therapy
†
Odds ratio of CAC progression (increase in CAC≥15%/year)
∆
Odds ratio of highest vs. 2 lower tertiles of epicardial adipose tissue,
Lipoprotein (a), OxPL/apoB, Ig G and Ig M autoantibodies to MDA LDL
and IC/apoB
Table 2 Relation of Garlic Therapy and Decrease in Atherosclerosis
25

(p<0.05). The adjusted risk of reduced mEAT was 7.69 (95%CI 2.52-23.25,
p=0.0001) in AGE-S as compared to placebo. Strong correlation between
decrease in mEAT and lack of CAC progression (r
2
=0.69, p=0.0001) was noted.
The decrease in EAT correlated with increases in OxPL/apoB (r
2
= 0.76), and
lipoprotein(a) (r
2
=0.67) levels, but negatively with IgM (r
2
= 0.90) and IgG (r
2
=
0.75) autoantibodies to malondialdehyde-low-density lipoprotein and apoB-
immune complexes (p <0.001 for all). After adjustment for risk factors, the
likelihood ratio of combined lack of CAC progression and reduction in mEAT was
12.82 (95%CI 4.05-41.66, p=0.0001) folds higher in AGE-S as compared to
placebo. This study reveals that AGE-S is independently associated with
reduction of mEAT, inflammatory biomarker and progression of CAC. Decrease
in mEAT was strongly correlated with increase in OxPL/apoB and lipoprotein (a)
and decreases in immune complexes.

4) Obesity And Intense Exercise And Moderate Caloric Restriction.
We studied the effects of 7-month intense exercise and moderate caloric
restriction on insulin-resistance, lipids, inflammatory biomarkers, carotid artery
distensibility index (CaDI) and carotid intima media thickness (CIMT) on 14
sedentary individuals with morbidly obesity. At 7-month follow-up, major
reductions in weight (-39%), body fat (-66%), serum insulin level (-52%), glucose
(-21%), high-sensitivity CRP(-81%), HbA1c(-11%), plasminogen activator
inhibitor-1(-49%), tumor necrosis factor receptor-II (-12%),CIMT (-25%) and
increases in CaDI (132%), adiponectin (94%), and Lipoprotein a (73%) were
26

observed (Table 4-6 and Figure 3). The improvement in CaDI was positively
correlated with increase in adiponectin, and Lipoprotein a, (r
2
=0.86, p=0.009), but
inversely with plasminogen activator inhibitor-1, tumor necrosis factor receptor-II,
CRP, and insulin resistance (r
2
=-0.64, p=0.01). Strong inverse correlation was
noted between decreases in CIMT and increases in CaDI (r
2
=0.65, p=0.001);
suggesting intense exercise with moderate caloric restriction over seven-month is
associated with a dramatic improvement in carotid vascular function,
atherosclerosis risk factors as well as a reduction in inflammatory biomarkers,
lipids, insulin resistance and CIMT.(Ahmadi N, Eshaghian S, et al., 2010)

3
27

4
5
28

FIGURE 3 Decrease in carotid intima media thickness with increase in lipoprotein (a) and
adiponectin, and decreases in insulin resistance and inflammation during the 7-month intense
exercise and diet program
29

CHAPTER THREE: COLLABORATIVE INTERVENTION
RESEARCH PLAN: APPROACH

Approach.
In this randomized clinical trial, the three related and overlapping specific aims
are directed to reduce atherosclerosis and improve obesity management by
understanding and developing models to assess: 1) To evaluate the change in
CDI, CIMT, CPV, MAC, oxidative stress and inflammatory biomarkers in
response to CI, 2) To assess the change in DNA methylation patterns,
expression and regulation of promoter regions of genes, and their interaction with
phenotypes in response to CI, and 3) Comparative biomolecular, therapeutic and
cost effectiveness analyses of 3 methods of CI to develop individualized
intervention models to improve management of morbidly obese individuals.
(Figure 4)
30

Recent United States national surveys showed significant increase in
prevalence of obesity and its associated complications in last two decades;
highlighting the necessity of proper prevention and management of obesity to
reduce obesity and its related complications including atherosclerosis, CAD and
mortality. The focus of this study is to investigate the underlying biologic,
phenotype and genotype determinant of successful management of obesity by
comparing the effectiveness of various combinations of collaborative integrative
interventions on reducing obesity and atherosclerosis. Comprehensive measures
of vascular function measured as coronary distensibility index (CDI),
atherosclerotic burden measured as carotid intima media thickness (CIMT) and
FIGURE 4 Collaborative Integrative Interventions
31

coronary plaque volume (CPV), metabolically active adipose tissue (MAC),
oxidative stress and inflammatory biomarkers se well as changes in DNA
methylation patterns, expression and regulation of promoter regions of genes in
the study participants provides fundamental information to specific differences
between different CI components in obesity treatment. The rate of change in
target variables and their interactions from baseline and 1-year follow-up study
will be available for analysis. Finally, individualized intervention models for
success obesity management based on the baseline and time-dependent
biologic, clinical and pharmacogenomics measures will be developed using
advanced statistical analyses.

Synopsis.
In this randomized clinical trial, 150 morbidly obese individuals’ ages 18 or older
and free of clinical cardiovascular disease will be recruited from the Obesity
Clinic of the Greater Los Angeles VA Health Care System, University of
California Los Angeles and Cedars Sinai Medical Center. One hundred and fifty
eligible subjects will be randomized to either of CI methods inclusive of MI plus
GBS, IE-MCR, or AOM (50 in each group), and receive these interventions for
the period of 1-year. (Figure 6) The eligibility criteria are determined based on the
primary hypotheses of this study to assess the biologic, clinical and
pharmacogenomics differences in response to different component of CI to
develop individualized interventional models to improve obesity management
(Figure 5). Exclusion criteria relates to history of prior known clinical CAD,
32

previous bariatric surgery or anti-obesity drugs, or incompatibility with certain
components of the trial. Before and during the study, the purpose, rationale, and
design of the study will be announced to all by flyers, mailings of letters and
brochures, followed by personal contacts via telephone or in person. Selected
subject will be followed before, during and after interventions, and all their clinical
and lab measures, carotid ultrasound, computed tomography, inflammatory
biomarkers, pharmacogenomics will be performed at baseline and at 1-year
follow-up. In addition, compliance to intervention and side effects, and adverse
events including myocardial infarction, stroke, hospitalization and death will be
assessed during the period of the study.

FIGURE 5 Eligibility Criteria
33

Procedures (Table 6)
Measures Details Base 1-yr
Blood Test
CBC, Chemistry, glucose, HbA1c, lipid profile,
LFT, GFR
x x
Inflammatory biomarkers x x
Pharmacogenomics x x
Carotid Ultrasound
Carotid Intima Media Thickness x x
Carotid artery Distensibility Index x x
Computed
Tomography
Coronary Plaque Volume and Composition x x
Coronary artery Distensibility Index x x
Metabolically Active Adipose Tissues x x
Demographics
Age, marital status, risk factors, socioeconomic
status
x x
Medications Anti-diabetic, anti-hypertension, statin, etc x x
Compliance Intervention, side effects x x
Calorie Assessment
Energy intake and expenditure, physical
activity status

Psychological status Satisfaction, Anxiety x x
Adverse Event Hospitalization, heart attack, stroke, death x x
H & P History and Physical Exams x x
FIGURE 6 Study Protocol Scheme
Table 6 Procedure Tables
34

P1) Carotid Ultrasound: High-resolution B-mode
ultrasound images of the right common-carotid
artery will be

obtained with a 7.5-MHz linear
array transducer. (Figure 7) CIMT will be
measured 5 to 10-mm below the common-
carotid bifurcation during mid-diastole in the M-
mode tracings by automated software, and
clinically-blinded expert readers. End-systole,
and end-diastole cross section area of common-
carotid will be calculated with the assumption
that the cross-section-area is circular (area=
(diameter/2)
2
x(π)). CaDI will be defined as:
CaDI=[(End-systole – End-diastole Cross-Sectional-Area of Common-Carotid )/((
End-diastole Cross-Sectional-Area of Common-Carotid) x( systemic-pulse-
pressure))x10
3
)]. (Ahmadi N et al., 2011) Plaque morphology will be assessed as
non-calcified, mixed and calcified in carotid ultrasound (Figure 8- mixed carotid
plaque). Plaque burden score will be calculated as a composite score of 1) semi-
quantified plaque volume (none, localized, intermediate, or diffuse), and type
(normal, non-calcified, mixed, or calcified) and severity of diseased carotid
(normal, mild, moderate, or severe).
FIGURE 7 Carotid Intima Media Thickness
FIGURE 8 Mixed Carotid Plaque
35

P2) Coronary Computed Tomography. Multidetector CT scanners will be used to
measure coronary plaque volume and composition, coronary artery distensibility
index (CDI) and metabolically active adipose tissues (MAT). Imaging will be
started 1 inch above the left main ostium and continued to 1 inch below the
bottom of the heart. ECG-triggered dose modulation will be applied in each case.
Cardiac data will be reconstructed from 5% to 95% of the R-R interval and with
10% intervals. Coronary vessels will be reviewed, and volume renderings and
curved multi-planar reformations will be done. CDI was defined as CDI = ( δlumen
CSA/[lumen CSA in end-diastole x central pulse pressure ) x 1000. The δlumen
CSA is defined as early-diastolic LAD CSA – end-diastolic LAD CSA. Adipose
tissue volumes will be measured from slice level 15 mm above the ostium of the
left main coronary artery to the bottom of the heart (Figure 9). Volumes of MAT
will be measured based on Hounsfield units (HU) cut off for regions of
metabolically active adipose tissues, which we have been validated before.
Based on extent of coronary plaque in contiguous segments in the 15-segment
AHA model, plaque volume will be classified as none, localized, intermediate, or
diffuse. Localized plaque volume will be defined as plaque confined to one
coronary segment. Intermediate plaque volume will be defined as plaque
extended into two contiguous segments. Diffuse plaque volume will be defined is
defined as plaque extended into more than two contiguous segments.(Ahmadi,
Nabavi, et al., 2011; Brodoefel et al., 2009; Korosoglou et al., 2010; Marwan et
al., 2011; Sabir et al., 2008)
36

A plaque burden score (PBS) will be developed to semi-quantify the plaque in
each participant using the AHA 15-segment model. PBS will be calculated as a
composite score of semi-quantified plaque volume, plaque composition (non-
FIGURE 9 Coronary Artery Distensibility Index
37

calcified, mixed and calcified) and severity of diseased coronaries (normal, mild
1-24%, moderate 25-49%, severe 50%+ luminal stenosis) based on American
Heart Association 15-segment model. (Range: 0-45) Total PBS is the sum of
evaluable coronary segments with individual plaque scores (Ahmadi, Nabavi, et
al., 2010; Ahmadi, Shavelle, et al., 2010; Pagali SR, 2010).
P3) Oxidative Stress Biomarkers. OxLDL biomarkers will be measured by
chemiluminescent enzyme-linked immunosorbent assay using the murine
monoclonal antibody E06, which binds to the phosphorylcholine head group of
oxidized but not native phospholipids. The data are presented as relative light
units per 100 ms. The OxLDL biomarkers are designed to be independent of
apoB (and LDL cholesterol) levels. Chemiluminescence enzyme-linked
immunosorbent assays will be used to measure IgG and IgM autoantibodies to
MDA-LDL and apoB-immune complexes (IC/apoB) as described previously.
Plasma Lp (a) and interleukin 6 (IL-6) levels will be measured by on standard
techniques. .(Tsimikas et al., 2007; Tsimikas et al., 2005; Tsimikas et al., 2004)
P4) Pharmacogenomics: For methylation analyses, DNA of white blood cells of
all participants will be assayed for bisulfite genomic sequencing of the exons.
Genomic DNA will be extracted. DNA samples will be treated with sodium
bisulfite. Bisulfite-modified DNA will be amplified with exon-specific primers.
PCR conditions will be as follows: an initial step at 95°C for 15 min, then 39
cycles of 95°C for 1 min, 60°C for 45 s, 72°C for 1 min; and a final step at 72°C
for 10 min. Afterwards the PCR product will be purified. The cleaned product will
38

be sequenced. Raw sequence data will be normalized. Quantitative methylation
rates will be calculated from the normalized sequence data. For gene expression
analysis, the frozen WBCs will be pulverized under liquid nitrogen, and total RNA
will be isolated. We will sequence small RNA libraries of WBC pre and post-
intervention using Illumina Genome Analyzer (Illumina, Inc.). Total RNA will be
reverse-transcribed into cDNA. Quantification of mRNA transcript will be
performed. The standard amplification protocol is consisted of a 5-min DNA
denaturation step at 95°C, followed by 40 amplification cycles consisting of 15 s
at 95°C and 1 min at 60°C. Relative transcript quantities (RQ) will be calculated
from the equation RQ = 2
-∆ ∆CT
(fold). (Christodoulou et al., 2011; Navarro et al.,
2009; Yu et al., 2011; Zaragosi et al., 2011)
P5) Clinical Measures. The list and dose of all medications, hospitalization,
intervention compliances and side effects will be recorded for each subject at
baseline and each visit. Subjects will undergo blood pressure and anthropometric
measurements, medical history and physical exam at each visit and follow up.
Major adverse cardiovascular events including heart attack, stroke and death will
be assessed during this study, and will be validated by medical records and
study physician.
P6) Calorie Assessment. Total energy intake will be calculated from 24-hour
dietary recalls collected up to four times over the course of a year and
approximately three months apart. Total energy intake will be averaged over all
24-hour recalls completed in the baseline year. Energy expenditure will be based
39

on a physical activity questionnaire that collected information about the number
of hours per week over a one-year period that subjects participate in various
physical activities.(Hanks et al., 2010; Howat et al., 1994) Physical activities will
be measured using cardiorespiratory fitness test. Individual activities will be
converted to MET values. (Santos et al., 2012)
P7) Psychological status. Beck anxiety and depression inventory questionnaires
will be used to assess psychological health status. Physical and mental health
will be assessed using validated questionnaires of SF-36.(Apolone & Mosconi,
1998; Groenvold, Klee, Sprangers, & Aaronson, 1997; Levenstein et al., 1993;
Llorens et al., 2010; Moncada et al., 2010)

Interventions.
Eligible participants will be randomized to a) MI plus IE-MCR, b) MI plus GBS,
or c) IM plus AOM for the period of 1-year.
I1) Motivational Interviewing. MI Values targets participants, to enhance their
autonomy for change. This strategy is designed to respect the developmental
processes of individuation and identity formation, and take into consideration the
participants’ readiness to change.
MI roadmap includes 1) Establishing Rapport, 2) Agenda Setting, 3) Exploring
Target Behavior, 4) Exploration of Values/Goals, 5) Exploration of Ambivalence
and Readiness to Change, 6) Negotiating a Change Plan/Eliciting Commitment,
and 7) Summary. Interventionists are encouraged to be flexible, using the
40

participant as a guide, while being faithful to the clinical style of MI. This general
structure is described below and outlined in Figure 10.

FIGURE 10 Motivational Interviewing
41

As part of Session 1, and consistent with the values-focus of MI, participants
complete a values-card sort task, using 39 value cards adapted for this study.
Interventionists present value cards to participants. On each card is written a
value and a clarifying statement, with blank cards included if participants wish to
add additional values. Participants rank the cards, according to their importance
to them, resulting in a selection of their top 5 values. The interventionist
encourages exploration of each value and develops discrepancy between the
stated value and their selected weight management behavior(s). Participants
discuss why their values are important to them, and explore what connection, if
any, they see between their ability to live out their values and their selected
health behavior. The interventionist throughout is MI-adherent, using open
questions, reflections, and affirmations to express empathy, develop discrepancy
and support self-efficacy in a non-confrontational, directive manner. While the
values clarification exercise is always included in this first session,
interventionists follow the roadmap outlined in Figure in their conduct of this MI
session, which includes a variety of MI techniques (i.e., exploring readiness to
change, eliciting change talk, and/or exploration of target behavior). If appropriate
based on participant readiness, behavioral goals are set by the end of this
session. In the MI session conducted at week 10 of CI, the MI Values
interventionist explores progress in CI, follows up on the values identified in the
initial session to examine how congruent current behaviors are with stated
values, and elicits participant ideas for change. As in Session 1, the MI
42

interventionist examines participants' motivation and confidence to make dietary
and/or exercise changes. To that end, the interventionist may use a variety of
clinical strategies in the encounters, such as importance and confidence rulers or
decisional balance. Interventionists use open-ended questions and reflections to
further explore ambivalence, with the goal to elicit change talk, resolve
ambivalence, highlight autonomy and support self-efficacy for change.
Throughout both MI sessions, the interventionist reflects the participants'
statements, and affirms the participants' efforts. This non-confrontational strategy
differs from typical clinician/patient interactions, in that information is only given if
it is directly requested by the patient, and the ideas for change are generated by
the patient.(Bean, Mazzeo, Stern, Bowen, & Ingersoll, 2011; Hettema, Steele, &
Miller, 2005)
I2) Intense Exercise and Moderate Calorie Restriction. Randomized subjects to
MI plus IE-MCR, will receive lectures on exercise and general dietary measures
including calorie counting. They will prepare their own food and completed daily
food and exercise journals. They will exercise 3 ± 2 hours/day, about half
supervised initially. Subjects will choose their own calorie intake but will be
instructed to aim for a protien:carbohydrate:fat ratio of 30:45:25 and to never go
below 70% their RDEE (21.6 x lean tissue (Kg) + 370).
I3) Gastric Bypass Surgery. Randomized subjects to MI plus GBS, will undergo
primary RYGB (open and laparoscopic). All subjects’ surgical procedure, the
43

potential long- and short-term complications, compliance with dietary and
physical activity will be followed for 12-month.
I4) Anti-Obesity Medication. A dose of 500 µg (10000 IU) recombinant human
chorionic gonadotropin (r-hCG) will be administered sublingual daily for the
period of 1-year.

Data Collection And Management.
The proposed Data Management Analysis Center (DMAC) will be housed
within the Statistical Consultation and Research Center (SCRC) in the
Department of Preventive Medicine at USC. A Director (Stan Azen, Ph.D.),
senior statistician (Wendy Mack, Ph.D.) will oversee the operation of the DMAC.
In particular, Drs. Azen, Mack and Ahmadi will supervise the management of all
data sources. They will be assisted by the Bioinformaticist and the Database
Manager. The DMAC team will work with the study investigators to finalize the
study data collection forms, develop a detailed Manual of Procedures, build a
computerized SQL database system, maintain and manage the Master
Database; produce monthly reports summarizing enrollment and data acquisition,
and investigator-approved secondary analyses; and participate in manuscript
preparation. The Bioinformaticist will be responsible for building the database
system. The project will utilize a web-based database similar to that used for the
Physical Therapy Clinical Research Network (PTClinResNet,
http://pt.usc.edu/clinresnet). The Database Manager will be responsible for
entering and managing the data from the various study components, exporting
44

the SQL database to the Statistical Analysis System (SAS) for reporting and
analysis purposes, editing and QCing the data, and producing monthly status
reports. Our specific aims are as following:

Specific Aim 1) To Evaluate The Change In CDI, CIMT, CPV, MAC, Oxidative
Stress And Inflammatory Biomarkers in Response To CI.
Synopsis. Here we seek to compare the difference a) functional atherosclerotic
changes as well as burden, b) fat mass and metabolically active adipose tissues,
and c) oxidative and inflammatory biomarkers between different CI approaches.

SA1a) To Assess Of The Change In CIMT Measured By Ultrasound, And CDI
and CPV Measured By Computed Tomography (CT),
SA1a) Sample size estimation. A measurable difference in carotid IMT in
response to 1-year CI intervention, is an outcome of interest for SA1a. We
recently reported that 7-month IE-MCR alone, reduced carotid IMT
significantly.(Table 7)(Ahmadi N, Eshaghian S, et al., 2010)

For a target of 20% decrease in caoritd IMT with collaborative integrative
intervention, 29 individuals per each of the main arms: 1) MI plus IE-MCR, 2) MI
plus GBS, and 3) MI plus AOM, with a type I error of one-sided significance level
of 0.05 (α=0.05) and a statistical power of 0.80 will be required.

Variable Baseline (N=14) Post IE-MCR (N=14) P value
Carotid IMT (mm) 0.728±0.194 0.542±0.132 0.001
TABLE 7 Power Calculation based on Change in Carotid IMT
45

SA1b) To Evaluate The Change In MAC And Fat Mass Measured By CT
SA1b) Sample size estimation. A measurable difference in fat mass in response
to 1-year CI intervention, is an outcome of interest for SA1b. We recently
reported that 7-month IE-MCR alone, reduced fat mass significantly.(Table
8)(Ahmadi N, Eshaghian S, et al., 2010)

For a target of 20% decrease in fat mass with collaborative integrative
intervention, 25 individuals per each of the main arms: 1) MI plus IE-MCR, 2) MI
plus GBS, and 3) MI plus AOM, with a type I error of one-sided significance level
of 0.05 (α=0.05) and a statistical power of 0.80 will be required.

SA1c) To Compare The Change Oxidative Stress And Inflammatory
Biomarkers In Response To CI Within And Across CI Methods.
SA1c) Sample size estimation. A measurable difference in tumor necrosis factor
receptor II (TNFRII) in response to 1-year CI intervention, is an outcome of
interest for SA1b. We recently reported that 7-month IE-MCR alone, reduced
TNFRII significantly.(Table 9)(Ahmadi N, Eshaghian S, et al., 2010)
Variable Baseline (N=14) Post IE-MCR (N=14) P value
Fat Mass (Ibs) 164±54 56±29 0.001
Variable Baseline (N=14) Post IE-MCR (N=14) P value
TNFRII 5.17±0.87 4.57±1.21 0.001
Table 8 Power Calculation based on Change in Fat

TABLE 9 Power Calculation based on Change in TNFRII
46

For a target of 20% decrease in fat mass with collaborative integrative
intervention, 30 individuals per each of the main arms: 1) MI plus IE-MCR, 2) MI
plus GBS, and 3) MI plus AOM, with a type I error of one-sided significance level
of 0.05 (α=0.05) and a statistical power of 0.80 will be required.
SA1 Statistical Analysis. The following steps will be conducted prior to
conducting statistical hypothesis tests: (a) data for all variables will be described
by frequency distributions, histograms, and summary statistics, both for the entire
sample and within key strata; (b) normalizing transformations will be applied as
necessary to skewed variables; (c) differences between the pre- and post-
intervention, and (d) differences between CI components will be examined.
Variables that differ between the groups will be considered as potential
covariates in subsequent statistical analyses. Student's t tests and Chi-square
tests will be used to assess biologic differences between groups. The primary
test of the differences in rate of change in CaDI, CDI, CIMT, CPV, MAT, fat mass
and inflammatory biomarker in: 1) post-intervention as compared to baseline, and
2) between interventions. In order to evaluate the intra- and inter- CI component
differences, we will use a series of three regression analysis models: A) Mixed
model regression; B) Generalized estimating equations for detailed exploratory
analyses and C) MCMC analyses for cross-validation of the earlier methods
together, and separately with a simulation model. A strength of the MCMC
approach is the ability to fit this entire combination of deterministic and stochastic
models. Subsequently the likelihood ratio test will be used to identify the
47

intervention-specific model for reducing atherosclerosis and obesity. These tests
will be two-tailed and conducted at the 0.05 alpha levels. The predictive
performance, the extent of over-fitting, and generalizability of model in predicting
future outcomes will be assessed through internal validation by bootstrapping
method.(Efron B & Tibshirani R, 1993) Regression analyses models will assess:
1) assess intervention specific rate of change in target variables, compliance and
side effects, 2) determinant of successful management of obesity, and
atherosclerotic regression in each intervention, 3) compare different CI
components to assess their differences in CaDI, CDI, CIMT, CPV, MAT, fat mass
and inflammatory biomarker , and 4) investigate the prognostic value of time-
dependent variables in each intervention to reduce atherosclerosis and improve
obesity management. To account for the effects of sample attrition, we will
perform the following analyses. First, for each respective study assessment time
point (i.e., at 6 and 12 months) we will perform baseline comparisons between
evaluable (i.e., non-dropouts) and non-evaluable (i.e., dropouts) study
participants on all variables. The results of these comparisons will provide
information about the generalizability of the results. Second, a sensitivity
analysis will be conducted to examine the robustness of the study results under
three conditions: (1) inclusion of evaluable participants only (i.e., excluding
dropouts); (2) inclusion of all study-enrolled individuals, with the assumption that
non-evaluable participants with no MACE after the time of dropout; and (3)
48

inclusion of all study-enrolled individuals who were followed for at least 12
months, with the use of imputed atherosclerotic change.

Specific Aim 2) To Assess The Change In DNA Methylation Patterns,
Expression And Regulation Of Promoter Regions Of Genes, And Their
Interaction With Phenotypes In Response To CI,
Synopsis. Here we seek to compare the difference in a) pharmacogenomics, b)
interaction between change in genotype and phenotype between different CI
approaches.

SA2a) To Evaluate The Change In DNA Methylation Patterns, Expression
And Regulation Of Promoter Regions Of Genes Critically Involved In The
Endothelial Function, Cholesterol Efflux, Atherosclerosis, And Adipose
Tissue In Response To CI Within And Across CI Methods,
SA2a) Sample size and power. A measurable difference in pharmacogenomic
changes in response to 1-year CI intervention, is an outcome of interest for
SA2a. For the effect size of 1.065 for up-regulation of endothelial cardio-
protective promoters, 36 individuals per each of the main arms: 1) MI plus IE-
MCR, 2) MI plus GBS, and 3) MI plus AOM, with a type I error of one-sided
significance level of 0.05 (α=0.05) and a statistical power of 0.80 will be required.

SA2b) Assessment Of Interaction Between Change In Genotype And
Phenotype,
SA2b) Sample size and power.
A measurable interaction between change in genotype and phenotype in
response to 1-year CI intervention, is an outcome of interest for SA2a. For the
target of 5% increase in coefficient of determination of predictor of successful CI,
49

based on likelihood ratio test, 40 subjects in each group with a type I error rate of
α=0.05 and a statistical power of 0.80 will be required
SA2 Statistical Analysis. To evaluate the a) pharmacogenomics and b) combined
phenotypes and genotypes interactions with CI, the following analyses will be
done. The phenotype and genotype interactions with CI will be assessed using
mixture model regression, generalized estimating equations, and MCMC
analyses based on models explained in detail in aim-1. Furthermore, a mixture
model approach will be used to concurrently detect main and interaction effects
of genotype and phenotype variables with CI through a likelihood ratio test (LRT).
In each gene/gene or gene/phenotype interaction, there are G cells. The G cells
will be derived from either a gene/gene or a gene/phenotype combination. Our
null hypothesis is whether G cells share the same binomial distribution between
CI components. The alternative hypothesis is that G cells don’t share the same
binomial distribution between CI components, but it may have different
appearances. E-M algorithm based clustering procedure and grouping
assignment will be used to test the alternative hypothesis. Previous studies
validated that mixture model’s likelihood ratio test is robust not only to small
sample size, but also to unequal sample size in various genotype and phenotype
subgroups. This also results in a fast algorithm for p-value calculations. In
addition to likelihood ratio tests, time-dependent receiver-operating characteristic
curves will be constructed for the following models: a) phenotype predictors
alone, b) genotype predictors, and c) phenotypes genotypes interactions. The
50

area under the curve (AUC) will be calculated to predict the ability of each model
to predict successful obesity management with an AUC of 0.50 indicating no
accuracy and a value of 1.00 indicating maximal accuracy.

Specific Aim 3) Comparative Biomolecular, Therapeutic And Cost
Effectiveness Analyses Of 3 Methods Of CI To Develop Individualized
Intervention Models To Improve Management Of Morbidly Obese
Individuals.
Synopsis. Here we seek to conduct comparative: a) biologic, clinical phenotype,
and genotype and b) cost, effectiveness research within and across CI methods
to develop individualized intervention models to improve management of
morbidly obese individuals, and reduce future events.

SA3a) To Compare The Biologic, Clinical Phenotype, And Genotype
Effectiveness Within And Across CI Methods,
SA3a) Sample size and power. A measurable difference in biologic, phenotype
and genotype between CI methods, is an outcome of interest for SA3a. For the
target of 10% difference between CI methods in increase in coefficient of
determination of biologic, clinical and genetic predictor of successful CI, based
on likelihood ratio test, 40 subjects in each group with a type I error rate of
α=0.05 and a statistical power of 0.80 will be required
SA3a) Intervention-Specific Mechanistic Models. Differential equation models for
pathways with stochastic distributions of individual’s oxidative stress and
inflammation, vascular dysfunction, atherosclerotic burden, plaque buildup,
plaque composition, pharmacogenomics, metabolic status, population
51

parameters, compliance to intervention and side effects will be combined and
fitted using MCMC methods to establish intervention-specific mechanistic model;
allowing assessment of contribution of each exposure to each pathway
,contribution of each pathway to obesity management and atherosclerotic
regression, and contribution of mechanistic model to predict determinants of
successful management of obesity, to improve quality of care in such cohorts
(Figure 11).

SA3b) To Compare Cost Effectiveness Within And Across CI Methods, To
Develop Individualized Intervention Models To Improve Management Of
Morbidly Obese Individuals, And Reduce Future Events.
SA3b) Cost Saving/Effectiveness Analysis. Medical treatment costs will be
compared between the CI components in management of obesity and reducing
atherosclerosis to generate measures of potential average cost savings
FIGURE 11 Mechanistic Models to Develop Individualized Intervention
52

associated with each method. Medicare costs will be assigned to medical
utilization records. To assess possible savings in medical costs that stem from
the each CI component, we will first perform both simple analysis of variance and
least squares analysis of individual patient medical costs. Analyses of
covariance will also be performed by adjusting for the effects of
demographic/background variables that are found to be significantly related to
cost beyond the .05 level in a preliminary stepwise regression analysis.
Intervention-specific cost for successful obesity management and reducing
atherosclerosis will be calculated, and cost-effective model based on the type of
intervention will be developed using MCMC methods.
SA3) Statistical Analysis. To conduct the comparative a) biologic, clinical
phenotype, and genotype and b) cost, effectiveness research (CER) within and
across CI methods, the following analyses will be done. For CER analyses, we
will fit a multiple levels hierarchical model to allow for dependence among the
responses observed for biologic, phenotype and genotype belonging to the same
CI method cluster (responses are clustered within each CI method and clustered
between CI methods). The mean response and 95%CI for each variable within
and between CI methods will be calculated using Markov chain Monte Carlo
(MCMC) methods. The rate of change in variable in response to CI, will be
categorized into three levels: “maximum change,” “moderately change,” and
“minimum or no change.” “Maximum change” will be those with a highest quartile
of change; “moderately change” will be those with an upper and lower
53

intermediate quartiles; and “minimum or no change” will be those with a lowest
quartiles of change in target variable. The CER be assessed using mixture model
regression, generalized estimating equations, and MCMC analyses based on
models explained in detail in SAs. Finally, likelihood ratio tests, time-dependent
receiver-operating characteristic curves will be constructed to compare
intervention specific individualized model with conventional risk factors.

54

CHAPTER FOUR: STUDY TIMELINES, ETHICS AND
ENVIRONMENT

Timeline.
This R01 grant would take 5 years to complete. Over a 3.5 year period, 150
morbidly obese individuals’ ages 18 or older and free of clinical cardiovascular
disease will be recruited from the Obesity Clinic of the Greater Los Angeles VA
Health Care System, University of California Los Angeles and Cedars Sinai
Medical Center. Eligible subjects will be randomized to either of CI methods
inclusive of MI plus GBS, IE-MCR, or AOM (50 in each group). All subjects will
receive weekly MI training for a year. MI plus IE-MCR will receive lectures on
exercise and general dietary measures including calorie counting. hey will
exercise 3 ± 2 hours/day, about half supervised, for a year. MI plus GBS will
undergo primary laparoscopic RYGB. MI plus AOB will receive r-HCG pills daily
for a period of 1-year. All subjects will be followed before, during and after
interventions. Subjects will undergo carotid ultrasound and CT at baseline and at
1-year follow-up, also their oxidative stress and inflammatory biomarkers as well
as genetic markers will be assessed. Study preparation and IRB will take place
over the first 6 months, and last 12 months will be required for statistical
analyses, mechanistic model testing, data cleaning and preparation of final
manuscripts. Novel intervention-specific mechanistic models based on biologic,
55

phenotype and genotype in morbidly obese individuals, using comparative
effectiveness research will be developed to improve monitoring response on anti-
obesity interventions, management of obesity, reduce in atherosclerosis, and
intervention compliance through intervention-specific individualized models for
morbidly obese individuals.

Ethical Aspects Of The Proposed Research
Confidentiality. Participation in this study will not involve loss of privacy, and
secured encrypted system will be used to conduct and analyze the data. All
records will be coded, all names and identifiable markers will be removed and a
code will be used throughout the study.
Benefit and Harm. Participants may choose not to participate in this study.
Refusal to participate or withdrawal from the study will not jeopardize the medical
care in any way. Subjects may not benefit directly from participation in this study;
however, the results of this study may allow better care of morbidly obese
individuals and may reduce atherosclerosis and improve obesity management in
such individuals in the future.
Categorization of Risk Level and Adverse Events. Risk level is low. The physical
risks from participation in this study are “moderate” given the low to moderate
probability of side effects of intense exercise with moderate caloric restriction,
and moderate to high intermediate side effects of gastric bypass surgery. These
risks will be pointed out in details in consent form, and all the potential risk and
adverse effects will be discussed with participants, and informed consent will be
56

obtained. As these results are collected, all adverse events will be identified and
reported to the PI or co-investigators immediately.
Inclusion of Women and Minorities. By design, women may include up to 50% of
subjects.
Inclusion of Children. Patients younger than 20 years are not included in this
study.

Environment.
Investigators will recruit eligible subjects in Cedars Sinai and UCLA/Greater
Los Angeles VA Healthcare System; benefiting from unique scientific
environment of VA, UCLA, and Cedars Sinai, and have complete institutional
administration support. Procedures will be done at GLAVA and Cedars Sinai
(DEXA Scans, Carotid Ultrasound, blood test, and clinical measures) and
University of Southern California (USC) (Statistical Analysis).

Study Administration And Personnel.
We have assembled an exceptionally accomplished cohort of scientists
including experts in atherosclerosis, obesity, and cardiovascular
epidemiology/statistics. Drs. Azen and Mack have validated and developed
statistical models for cardiovascular risk using novel atherosclerotic measures
and will be largely responsible for model creation. Drs. Siegel, Hodis, Ebrahimi
and Ahmadi are atherosclerosis and cardiovascular imaging experts, and Drs.
Huizenga and Mehran are obesity experts and this group of scientists have done
57

significant validation work developing mechanistic models to measure novel
markers of atherosclerosis, and obesity interventions as well as multiple projects
related to CV epidemiology and statistics, especially in the context of mechanistic
measures, and outcome measures as well as obesity preventive initiative study.

58

CONCLUSION

Overall Summary And Conclusions.
This study will integrate our understanding of the underlying biologic, clinical
and pharmacogenomics differences in response to different collaborative
integrative intervention methods including motivational interviewing (MI) plus
Gastric bypass surgery (GBS), MI plus intense exercise and moderate caloric
restriction (IE-MCR), or MI plus anti-obesity medications (AOM) to manage
obesity. Finally, comparative biologic, therapeutic and cost effectiveness of each
CI component will be performed. Furthermore, it contributes to develop
intervention-specific individualized intervention to manage obesity.
These variables are central to understanding successful management of
obesity and reduction of atherosclerosis in morbidly obese individuals. The
results will clarify some of the key underlying mechanisms of these interventions.
This work builds on a solid intellectual and methodological foundation resulting
from our previous studies, and we have the capability and background
information required for conducting this trial.

59

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Abstract (if available)

Abstract Background. Obesity is prevalent and linked with inflammation, insulin resistance, dyslipidemia, atherosclerosis, and associated with significant morbidity and mortality. The economic burden of obesity-related illnesses is substantial, with estimates ranging from 2% to 7% of the total US health care expenditures and billions of dollars in direct and indirect costs to society. This goal will be accomplished by collaborative integrative interventions (CI) in morbidly obese individuals in which eligible subjects will be randomized to MI plus Gastric bypass surgery (GBS), intense exercise and moderate caloric restriction (IE-MCR), or anti-obesity medications (AOM). ❧ Importance/Significance. There is a cumulative increase in the rate of obesity, up to two thirds of the US population. This randomized clinical trial will assess: 1) the change in biologic and clinical phenotypes in response to CI, 2) the change in genotypes in response to CI, and 3) Comparative biomolecular, therapeutic and cost effectiveness analyses of methods of CI to develop individualized intervention models to improve management of morbidly obese individuals. vascular function measured as coronary distensibility index (CDI), atherosclerotic burden measured as carotid intima media thickness (CIMT) and coronary plaque volume (CPV), metabolically active adipose tissue (MAC), oxidative stress and inflammatory biomarkers se well as changes in DNA methylation patterns, expression and regulation of promoter regions of genes provides fundamental information to assess the beneficial effects within and across CI methods on obesity management. This study investigates the underlying determinant of successful management of obesity by comparing biologic, clinical phenotype, genotype and cost effectiveness of CI methods, also enhances individualized anti-obesity interventions. ❧ Method. The CI methods are hypothesized to improve CDI and reduce CIMT, CPV and MAC, also increase up-regulation of cardio-protective genes. Over a 3 year period, 150 morbidly obese individuals’ ages 18 or older and free of clinical cardiovascular disease will be recruited from the Obesity Clinic of the Greater Los Angeles VA Health Care System, University of California Los Angeles and Cedars Sinai Medical Center. One hundred and fifty eligible subjects will be randomized to either of CI methods inclusive of MI plus GBS, IE-MCR, or AOM (50 in each group). All subjects will receive weekly MI training for a year. MI plus IE-MCR will receive lectures on exercise and general dietary measures including calorie counting. They will prepare their own food, with protien:carbohydrate:fat ratio of 30:45:25 and over 70% their resting daily energy expenditure, and completed daily food and exercise journals. They will exercise 3 ± 2 hours/day, about half supervised, for a year. MI plus GBS will undergo primary laparoscopic RYGB. MI plus AOB will receive xx pills daily for a period of 1-year. All subjects will be followed before, during and after interventions. Subjects will undergo carotid ultrasound and CT at baseline and at 1-year follow-up, also their oxidative stress and inflammatory biomarkers as well as genetic markers will be assessed. CI methods’ compliance and side effects will be evaluated.

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Creator Ahmadi, Naser (author)

Core Title Comparative biomolecular and therapeutic effectiveness of collaborative integrative intervention in morbidly obese individuals

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School Keck School of Medicine

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Publication Date 09/19/2012

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Tag anti-obesity medications,atherosclerosis,collaborative integrative interventions,comparative biomolecular,fat mass,gastric bypass surgery,genomics,intense exercise and moderate caloric restriction,motivational interviewing,OAI-PMH Harvest,therapeutic and cost effectiveness analyses

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