ATHEROSCLEROSIS:

UNDERSTANDING PATHOGENESIS
AND CHALLENGE FOR TREATMENT

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 ATHEROSCLEROSIS:
UNDERSTANDING PATHOGENESIS
AND CHALLENGE FOR TREATMENT

SLAVICA MITROVSKA
SILVANA JOVANOVA
INGE MATTHIESEN
AND
CHRISTIAN LIBERMANS

Nova Biomedical Books

New York
Copyright © 2009 by Nova Science Publishers, Inc.

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 Contents

Preface vii
Chapter I Introduction 1
Chapter II Impaired Endothelial Function 3
Chapter III Inflammatory Pathways Promote Atherosclerosis 5
Chapter IV The Composition of the Atherosclerotic Plaque 7
Chapter V Thrombogenesis 9
Chapter VI Therapeutic Approaches 11
Chapter VII Treatment of the Established Risk Factors 13
Conclusion 15
References 17
Index 21
 Preface

Atherosclerosis is a chronic inflammatory disease that affects medium and

large-sized arteries. It begins after birth and the progression depends on several
factors – traditional triad: hypertension, hyperlipidemia and diabetes mellitus,
then age, sex, smoking and sedentary life-style. At the beginning atherosclerosis is
asymptomatic and we cannot estimate appropriately its frequency, but its
complications – coronary artery diseases, cerebrovascular diseases, peripheral
arterial diseases, which occur late, are responsible for more than half of the yearly
mortality in the world. Unfortunately, sudden cardiac death may be the first
clinical manifestation.
The incipient event is endothelial dysfunction, as a result of injury, caused by
high level of cholesterol [especially low-density-lipoprotein LDL],
hyperglycemia, hypertension, smoking, infectious agents, and toxins. Endothelial
cells overexpress adhesion molecules – vascular cell adhesion molecule–1
[VCAM-1] and increases recruitment of inflammatory cells– monocytes [Mo], T-
cells and subsequent release of monocyte chemo–attractant protein–1 [MCP-1]
that results in additional leucocytes recruitment. Injured endothelium allows
migration of inflammatory cells that release cytokines and lipids into the intima.
That leads to cytokine-mediated progression of atherosclerosis and oxidation of
LDL. Macrophages [MP] take up oxi-LDL and form foam-cell. They have
metabolic activity and produce cytokines, proliferation of smooth muscle cells
and formulate athero-fibrose plaque. Atherosclerotic plaque is composed of
superficial layer – fibrose cap and lipid core, that consists of foam cells,
extracellular lipid and necrotic cellular debris. It progresses as a result of
accumulation of lipid and proliferation of smooth muscle cells and results in
luminal narrowing of the arteries which leads to compromised blood and oxygen
supply to the tissues. The gradually growing atherosclerotic plaques have thick
viii Slavica Mitrovska, Silvana Jovanova, Inge Matthiesen et al.

fibrose cap and are stable. They cause symptoms of stable angina. Rapidly
growing plaques cause unstable coronary artery disease. These plaques are mainly
composed of lipids and have tiny fibrose cap that is prone to fissuring or rupture.
Intraplaque hemorrhage from microvessels in plaque initiate platelet adhesion and
activation of coagulation cascade that leads to platelet thrombus formation, i.e.
promote thrombogenesis.
Knowledge of the pathogenesis of the atherothrombosis modifies the
diagnostic and therapeutic approach.
Conclusion: Our attention should be focused on the management of three
points:

1. Endothelial dysfunction [correction of modified risk factors:

hypertension, hyperlipidemia, diabetes mellitus, life-style-smoking,
physical activity and food],
2. Atherosclerosis [modification of the inflammatory cascade, i.e.
elimination of inflammatory pathways and inhibition of oxidation of
LDL],
3. Thrombogenesis [inhibition of platelet adhesion, activation and
aggregation].

Keywords: atherosclerosis, endothelial dysfunction, inflammatory pathways,

thrombogenesis.
 Chapter I

Introduction

Atherosclerosis is a chronic inflammatory disease that affects medium and

large-sized arteries. It begins after birth, initially it is a silent process but it
progresses during the person’s life. The atherosclerotic lesions are a result of
continuum molecular and cellular interaction between vessel wall and blood
constituents, release of number of signaling pathways and activation of the
inflammatory and coagulation cascades that lead to structural changes. At the
beginning atherosclerosis is asymptomatic and we cannot estimate appropriately
its frequency. But, in some people atherosclerosis has rapid progress and triggers
a vicious circle that leads to clinical manifestations of coronary artery diseases,
cerebrovascular diseases, and peripheral arterial diseases. Unfortunately, sudden
cardiac death may be the first clinical manifestation. The increasing incidence
makes the atherosclerosis a leader of morbidity and mortality in the developing
world.
According to the American Heart Association, more than 11 million people
suffer from coronary artery disease [CAD] in USA, 30% have carotid artery
disease, 1.5 million myocardial infarctions per year, more than 200,000 deaths per
year caused by cerebrovascular diseases [1].
The other thing that should be a concern is the increasingly younger age
group having onset of symptoms, as early as 35 years old. The progress of
atherosclerosis depends on several factors – traditional triad: hypertension,
hyperlipidemia and diabetes mellitus, than age, sex, stress, smoking and sedentary
life-style [2].
 Chapter II

Impaired Endothelial Function

The incipient changes occur in the endothelium and the earliest step is
impaired endothelial function. Endothelium is an inner layer of the vessel wall
that has an active role to respond to various stimuli. It acts as an endocrine organ
that has secretory role and it takes place in the process of inflammation,
hemostasis and fibroproliferative process. Also, endothelium regulates the vessel
wall tonus by release endothelium derived relaxing [EDRF] and constrictive
factors. The vasodilatation is providing by EDRF – nitric oxide [NO], produced
by NO synthase enzyme [type III eNOS], whereas vasoconstriction is mediated by
endothelin-1 [ET-1] and thromboxane A2. The imbalance between vasodilatative
and vasoconstrictive substances leads to the impairment of endothelial cell
function. This is the first stage of atherosclerotic process – lack of activity of
endothelium derived NO and impaired vascular relaxation. In the setting of
hypertension, hyperlipidemia [especially high level of LDL-C], diabetes mellitus,
genetic alterations, smoking, toxins, infectious agents, the blood flow became
turbulent and provoked a number of insults to the endothelium [3].
 Chapter III

Inflammatory Pathways
Promote Atherosclerosis

As a “response to injury” the endothelium becomes active and initiates a

cascade of subsequent events, which are compensatory mechanisms to keep the
homeostasis. If the influence of provocative agents continues excessively, than
these mechanisms overdrive normal properties of the endothelium and lead to the
development of atherosclerotic plaque. The activated endothelium over expresses
adhesion molecules, as vascular cell adhesion molecule-1 [VCAM-1] and
increases recruitment of inflammatory cells - monocytes [Mo], T-cells and
subsequent release of monocytchemo-attractant protein-1 [MCP-1] that results in
their differentiation into macrophages [MP] [4].
In the acute phase, the inflammatory cells secrete a number of cytokines,
mostly interleukins – IL-1ß, IL-6, IL-8, than tumor necrosis factor- α [TNF-α],
interferon-γ [IFN-γ] and transforming growth factor-ß [TFG-ß] [5]. They increase
permeability of the endothelium to lipoproteins, especially low-density-
lipoproteins [LDL-C] and they have enhanced migration through the endothelial
membrane into subendothelium. LDL deposit initiates additional induction of
numbers MP and release of cytokines [especially IL-1], hydrolytic enzymes and
chemokines, growth factors and a vicious circle of inflammation starts [6].
Increased accumulation of MP is associated with increased level of fibrogen and
C-reactive protein [CRP]. It is believed that CRP helps the MP in the process of
phagocytosis.
Intra intimal LDL undergoes oxidation [oxidant stress] by oxidant
mechanisms that involve hydrogen peroxide and free radicals. MP recognizes and
phagocyte oxidized low-density-lipoproteins [oxi-LDL] through scavenger
6 Slavica Mitrovska, Silvana Jovanova, Inge Matthiesen et al.

receptors [7]. Accumulation of oxi-LDL and cholesterol esters in MP leads to

formation of foam cells. Oxidized LDL have toxic effects. They produce free
radicals that reduce activity of NO-synthase and inactivation of NO leads to
vasoconstriction [8].
The foam cells have metabolic activity, secrete TGF-ß, stimulating the
proliferation of smooth muscle cells, fibroblasts, collagen and elastin and form
fibrous cap over the lipid collection. Thus, the atherofibrous plaque is formed [9].
 Chapter IV

The Composition of the

Atherosclerotic Plaque

Atherosclerotic plaque progresses as a result of the progressive accumulation

of lipids and proliferation of smooth muscle cells. As long as injurious agents
persist, the affected endothelium reacts with abnormal inflammatory and
fibroproliferative response, triggering the progression of atherosclerotic plaque, as
well as the disease progression. Development of plaque deforms the arterial wall.
The gradually growing plaques cause thickening of the artery wall. The
arterial wall becomes rigid. At the beginning they do not compromise arterial
circulation. These plaques are angiographically invisible and according to the
American Heart Association, are classified as type IV and V-a [10]. At that stage,
the lumen of the artery remains unaltered due to “remodeling,” compensatory
dilatation of the wall, termed – Glagov phenomenon. Further enlargement of the
lesion results in luminal narrowing and compromising of the blood and oxygen
supply [11].
The gradually growing atherosclerotic plaques have a thick fibrous cap. They
are stable and when the narrowing of the lumen is more than 50%, cause the
symptoms of chronic stable angina. Clinicians note that these patients have better
prognosis despite critical diminution of the coronary artery flow. Contrary,
potentially dangerous lesions are usually nonocclusive. Thus, retrospective
analyses of angiographic observations revealed that almost 2/3 of patients with
acute coronary syndromes [unstable angina and myocardial infarction] have low-
grade stenosis less than 70% [mostly < 50%]. Morphologic examinations have
shown that these plaques are composed mainly of lipids and have a tiny fibrous
cap [12].
8 Slavica Mitrovska, Silvana Jovanova, Inge Matthiesen et al.

These findings lead our attention to the other direction, to the composition of
the atherosclerotic plaque, as an important predictor of adverse cardiac events.
In 1992, James Muller introduces the term “vulnerable” plaque. It is a
morphologic description and concerns the cellular and molecular characteristics of
the atherosclerotic plaques that are prone to rupture [13].
Peter Libby et al. describe vulnerable plaque as a lesion consisting of a central
lipid-rich core, surrounded by a tiny fibrous cap [14]. Davies et al. estimate that
the lipid core is 30-40% of the vulnerable plaque volume [15].
Lipid-rich core is composed of lipid-laden foam cells, necrotic cellular debris,
extracellular lipid, free and esterified cholesterol and cholesterol esters.
The thickness of the fibrous cap is a second condition for stability/instability
of the plaque. The tiny cap is collagen-deficient and also contains less
proteoglicans. These things make the cap much more susceptible to destroying
enzymes – matrix metalloproteinase (MMPs) that include collagenase and
gelatinase and prone to disruption. Burne et al. define the fibrous cap as
vulnerable if its thickness is less than 65 μm [16].
Several results from coronary atherectomy have shown that the culprit lesion
in patients with unstable angina has increased neovascularization. These vasa
vasorum that proliferate within the plaque are fragile and cause intraplaque
hemorrhage with secondary rupture [17].
Concerning the mechanism of instability of atherosclerotic plaque, most of
the theories accentuate the imbalance between presences of normal and
inflammatory cells [18]. Thus, inflammatory cells, especially T-Ly, have a
tendency to localize in the “shoulders” of the plaque. These sites are lesion prone
sites. T-Ly produce cytokine, CD40 ligand, IFN-γ that impairs collagen synthesis
and IL-1β and IL-4 stimulate MP to produce MMP that degrade the fibrous cap.
The result of this activity is plaque rupture or plaque erosion and exposition of
thrombogenic substances of the core to the blood [19].
 Chapter V

Thrombogenesis

Normal endothelium maintains the platelets in a resting state by producing

prostacyclin and NO. Loss of endothelium exposes the subendothelium to the
blood constituents and initiates the activation of coagulation cascade [20]. Thus,
the procoagulant milieu favors thrombus formation. The subendothelium releases
von Willebrand factor and other adhesive proteins that bind to glycoprotein
receptor Ib [GP Ib] on the platelet surface and provoke platelet adhesion to the
subendothelial collagen. Furthermore, adhered platelets became active, secrete
adenosine-diphosphate [ADP] and number of mediators-cytokines, Thrombocyte
derived growth factor, Thrombocyte factor-4, C-reactive protein, TGF- β,
Placental growth factor [PlGF] and together with thrombin promote platelet
aggregation [21].
Final step in the process of thrombogenesis is the activation of the GP IIb/IIIa
receptors of the platelet surface, and together with fibrinogen make tight
connection between platelets. That leads to thrombus formation [22]. This is a
defensive mechanism, to protect the organism from bleeding. Activation of
platelets involves triggering of internal signaling pathways, as a releasing of
adenosine diphosphate [ADP], serotonin, calcium and recruitment of more
platelets. But sometimes those triggers became uncontrolled and thrombus
formation culminates in thrombosis. The final outcome is occlusion of the artery
and consecutive events – stable, unstable angina or myocardial infarction.
Thus thrombogenesis has become the second most important process in
pathogenesis of acute coronary syndrome [23].
 Chapter VI

Therapeutic Approaches

The base of human physiology is to keep the balance between restoring and
destroying processes. For this purpose, each process in the human body consists
of pro and contra mechanisms [proinflammatory and anti-inflammatory,
procoagulant and anticoagulant elements]. The aim is to maintain the equilibrium
and to provide normal function for each organ.
The nature of the processes of atherosclerosis and thrombogenesis, as well as
their alterations and signaling pathways, are a challenge for observation and
action [24].
Considering that atherosclerosis begins at birth and progresses during one’s
lifetime, maybe we should accept it as a part of biologic evolution, as a part of the
natural aging process. The question is why, what and when this process became
out of control? Why some people develop rapid process of atherosclerosis? What
are the provocative factors that trigger uncontrolled inflammatory, prothrombotic
and fibroproliferative signaling pathways[25]?
Exploring these reasons, we review the current therapeutic modalities. Thus,
the mechanical revascularization techniques [angiography/stenting as well as by-
pass surgery] are palliative treatments. They have excellent results in reducing the
incidence of adverse cardiac events (recurrent angina, myocardial [re]infarction,
heart failure, cerebrovascular insult, death), but these are a secondary prevention.
The process of atherosclerosis continues [in-stent restenosis, graft stenosis]. So,
we need to focus on primary prevention. Peter Libby suggests, “the concept of
interventional cardiology must expand beyond mechanical revascularization to
encompass preventive interventions that forestall future events” [26].
In this regard we need to focus our attention in three directions:
12 Slavica Mitrovska, Silvana Jovanova, Inge Matthiesen et al.

1. Correction of the established risk factors: [control the blood pressure,

hyperlipidemia, diabetes mellitus, lifestyle modification, smoking,
physical activity and food],
2. Modification of the inflammatory cascade, i.e. elimination of
inflammatory pathways and inhibition of oxidation of LDL. To enter
deep into mechanisms of inflammation and address oxidative stress as a
root cause,
3. Inhibition of platelet adhesion, activation and aggregation.
 Chapter VII

Treatment of the Established

Risk Factors

Treating casual factors (hypertension, diabetes mellitus and hyperlipidemia)

is the most helpful means to control and modify the disease’s progress. Smith S.
and colleagues states “aggressive risk factors management improves survival,
reduces recurrent events and the need for interventional procedures and improves
quality of life for patients with atherosclerotic vascular disease” [27].
Hypertension provokes endothelial dysfunction and accelerates
atherosclerosis. Angiotensin II, the enzyme that is elevated in patients with
hypertension, causes vasoconstriction. Diminishing the concentration of this
enzyme with ACE inhibitors, prevents stimulation of smooth muscle cell and
inhibition of myointimal proliferation.
Also, ACE inhibitors inhibit the breakdown of bradykinin, stimulant of nitric
oxide release and promote a vasodilatory effect. Their antiproliferative, anti-
inflammatory and vasodilatory effects modulate atherosclerotic process [28,29].
The advanced glycosylation end products, in patients with diabetes mellitus,
change the phenotype characteristics of endothelial cells. They increase adhesion
of Mo on their surfaces and increase the adhesion of platelets their activation and
aggregation. Patients with insulin resistance have high level of markers of
inflammation (CRP), haemostasis (coagulation factors VII–IX, von Willebrand
factor) and marker of endothelial dysfunction (tissue plasminogen activator [t-PA]
antigens). Good glycemic control (introducing the insulin) will interfere with
decreasing the inflammation, controlling the atherosclerotic lesions and thrombus
formation [30].
14 Slavica Mitrovska, Silvana Jovanova, Inge Matthiesen et al.

Lifestyle modification (especially in regards to fatty food, smoking, sedentary

lifestyle) contribute significantly to keep control of atherosclerosis.
Currently, the main focus is to reduce oxidative stress, oxidative damage to
the endothelial cells as a base of inflammation and development of
atherosclerosis. Advances in the understanding of molecular basis of
atherosclerosis have shown that inflammatory pathways are included in each step
of atherogenesis. Addressing the oxi-LDL, as a very active and having a toxic
effect on endothelium, can slow the atherosclerotic progression. In many studies,
early institution of statins, 3-hydroxy-3-metylgluteryl coenzyme A [HMG-CoA]
reductase inhibitors, have shown a significant anti-inflammatory effect [31].
They have an important role in the treatment of atherosclerosis, increasing the
concentrations of anti-inflammatory cytokines [IL-10] and decreasing the
concentrations of proinflammatory cytokines [IL-1 and CRP]. In this way, statins
have made an important contribution in reducing the consequences of
atherosclerosis as well as overall mortality [32].
As thrombogenesis is a part of atherosclerotic disease, the inhibition of
platelet activation and thrombin generation also contributes to improve clinical
outcomes.
The analyses of several studies underlie potential benefits of inhibitors of
adenosine-di-phosphate (Clopidrogrel, Ticlopidine) and inhibitors of GP IIb/IIIa
receptors (Abciximab, Eptifibatide, Aggrastat) in reducing the risk of death in
patients with ischemic heart disease and atherosclerosis [33, 34].
 Conclusion

Atherosclerosis is an ongoing problem in modern society. Many factors that

are established as risk factors for atherogenesis cause activation of the cells and
signaling pathways involve in the process of inflammation. Despite many studies
that offer potentionally valuable information in this regard, we still need to enter
deep into pathogenesis of inflammation and search for trigger mechanisms.
Understanding the pathogenesis of atherosclerosis will contribute to introduce
more effective novel therapies that may modulate the course of atherosclerosis.
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 Index

atherosclerosis, vii, viii, 1, 11, 13, 14, 15, 18,

A 19
atherosclerotic plaque, vii, 5, 7, 8
ACC, 19
atherosclerotic vascular disease, 13
ACE, 13, 19
attention, viii, 8, 11
ACE inhibitors, 13, 19
activation, viii, 1, 9, 12, 13, 14, 15, 18
acute, 5, 7, 9, 17, 18 B
acute coronary syndrome, 7, 9, 17, 18
adenosine, 9, 14 benefits, 14
adhesion, vii, viii, 5, 9, 12, 13, 18 beta, 17
ADP, 9 biologic, 11
age, vii, 1 birth, vii, 1, 11
agents, vii, 3, 5, 7 bleeding, 9
aggregation, viii, 9, 12, 13 blood, vii, 1, 3, 7, 8, 9, 12
aging, 11 blood flow, 3
aging process, 11 blood pressure, 12
American Heart Association, 1, 7, 17, 18 bradykinin, 13
angina, viii, 7, 8, 9, 11, 19 breakdown, 13
angiography, 11
angiotensin, 13, 19
Angiotensin II, 13 C
angiotensin-converting enzyme, 19
anticoagulant, 11 CAD, 1
anti-inflammatory, 11, 13, 14 calcium, 9
apoptosis, 17 cardiology, 11
arteries, vii, 1 cardiovascular, 18
artery, vii, viii, 1, 7, 9, 18 CD40, 8
asymptomatic, vii, 1 cell, vii, 3, 5, 13, 17, 18
atherogenesis, 14, 15 cell adhesion, vii, 5
cell cycle, 18
22 Index

cerebrovascular, vii, 1, 11
cerebrovascular disease, vii, 1
E
cerebrovascular diseases, vii, 1
elastin, 6
cerebrovascular insult, 11
electronic, iv
chemokines, 5
electrostatic, iv
cholesterol, vii, 6, 8, 19
endocrine, 3
chronic, vii, 1, 7
Endothelial, v, vii, viii, 3
circulation, 7
endothelial cell, 3, 13, 14, 17
classification, 18
endothelial cells, 13, 14, 17
classified, 7
endothelial dysfunction, vii, viii, 13, 17
clinical, vii, 1, 14
endothelin-1, 3
coagulation, viii, 1, 9, 13
endothelium, vii, 3, 5, 7, 9, 14
coagulation factor, 13
enlargement, 7
coagulation factors, 13
enzyme, 3, 13, 19
coenzyme, 14
enzyme inhibitors, 19
collagen, 6, 8, 9
enzymes, 5, 8
collagenase, 8
equilibrium, 11
complications, vii
erosion, 8, 18
composition, 8, 18
esters, 6, 8
concentration, 13
evolution, 11
Congress, iv
examinations, 7
control, 11, 12, 13, 14, 18
expert, iv
coronary artery disease, vii, viii, 1
extracellular, vii, 8, 18
coronary heart disease, 17
extracellular matrix, 18
coronary thrombosis, 18
C-reactive protein (CRP), 5, 9, 13, 14
cytokine, vii, 8 F
cytokines, vii, 5, 9, 14, 17
failure, 11
fibrinogen, 9
D
fibroblasts, 6
fibrose cap, vii
Dallas, 17
fibrous cap, 6, 7, 8
death, vii, 1, 11, 14
flow, 3, 7
deaths, 1
foam cells, vii, 6, 8, 17
definition, 18
food, viii, 12, 14
degrading, 17
Fox, 19
density, vii, 5
free radical, 5
diabetes, vii, viii, 1, 3, 12, 13
free radicals, 5
diabetes mellitus, vii, viii, 1, 3, 12, 13
diabetic, 19
diagnostic, viii G
differentiation, 5
disease progression, 7 gelatinase, 8
generation, 14
genetic, 3
 Index 23

genetic alteration, 3 inflammatory disease, vii, 1

Geneva, 17 inhibition, viii, 12, 13, 14
glycoprotein, 9, 18, 19 inhibitors, 14, 19
glycosylation, 13 initiation, 18
growth, 5, 9, 17 injury, iv, vii, 5
growth factor, 5, 9, 17 instability, 8
growth factors, 5 insulin, 13, 19
insulin resistance, 13, 19
insults, 3
H interaction, 1
interferon, 5
haemostasis, 13
interferon-γ, 5
heart, 1, 7, 11, 17, 18, 19
interleukins, 5
heart disease, 14, 17, 18
intima, vii
heart failure, 11
ischemic, 14, 18, 19
hemorrhage, viii, 8
ischemic heart disease, 14, 18
hemostasis, 3
histological, 18
homeostasis, 5 L
human, 11, 17, 18
hydrogen, 5 LDL, vii, viii, 3, 5, 12, 14, 17
hydrogen peroxide, 5 lead, 1, 5, 8
hypercholesterolemia, 18 lesions, 1, 7, 13, 18
hyperglycemia, vii lifestyle, 12, 14
hyperlipidemia, vii, viii, 1, 3, 12, 13 lifetime, 11
hypertension, vii, viii, 1, 3, 13 ligand, 8
lipid, vii, 6, 8
lipid core, vii, 8
I lipids, vii, 7
lipoprotein, vii
ICAM, 18
lipoproteins, 5, 17
IFN, 5, 8
low-density, vii, 5, 17
IL-1, 5, 8, 14
low-density lipoprotein, 17
IL-10, 14
lumen, 7
IL-4, 8
luminal, vii, 7
IL-6, 5
IL-8, 5
inactivation, 6 M
incidence, 1, 11
induction, 5 macrophages, 5
infarction, 7, 9, 11, 18 magnetic, iv
infectious, vii, 3 management, viii, 13
inflammation, 3, 5, 12, 13, 14, 15 matrix, 8, 17, 18
inflammatory, vii, viii, 1, 5, 7, 8, 11, 12, 13, matrix metalloproteinase, 8, 17
14, 19 MCP, vii, 5
inflammatory cells, vii, 5, 8 MCP-1, vii, 5
24 Index

mechanical, iv, 11 oxide, 3, 13

mediators, 9 oxygen, vii, 7
medicine, 18
men, 18, 19
metabolic, vii, 6, 19 P
metabolic syndrome, 19
palliative, 11
metalloproteinase, 8, 17
pathogenesis, viii, 9, 15, 18
microvessels, viii
pathways, viii, 1, 9, 11, 12, 14, 15
migration, vii, 5
patients, 7, 8, 13, 14, 17, 19
MMP, 8
peripheral arterial disease, vii, 1
MMPs, 8
peripheral arterial diseases, vii, 1
modalities, 11
permeability, 5
modern society, 15
peroxide, 5
molecules, vii, 5, 18
phagocyte, 5
monocyte, vii
phagocytosis, 5
monocytes, vii, 5
phenotype, 13
morbidity, 1
Philadelphia, 18
morphology, 18
phosphate, 14
mortality, vii, 1, 14
physical, viii, 12
muscle, vii, 6, 7, 13
physical activity, viii, 12
muscle cells, vii, 6, 7
physiology, 11
myocardial infarction, 1, 7, 9, 18
plaque, vii, 5, 6, 7, 8, 18
plaques, vii, 7, 8
N plasminogen, 13
platelet, viii, 9, 12, 14, 18, 19
natural, 11 platelet aggregation, 9
necrosis, 5 platelets, 9, 13
neovascularization, 8, 18 preparation, iv
New York, iii, iv pressure, 12
nitric oxide, 3, 13 prevention, 11
NO, 3, 6, 9 preventive, 11
NO synthase, 3 procedures, 13
normal, 5, 8, 11 procoagulant, 9, 11
prognosis, 7
progressive, 7
O proinflammatory, 11, 14, 19
proliferation, vii, 6, 7, 13
observations, 7
promote, viii, 9, 13
occlusion, 9
property, iv
organ, 3, 11
protein, vii, 5, 9
organism, 9
proteins, 9
oxidation, vii, viii, 5, 12
oxidative, 12, 14, 17
oxidative damage, 14
oxidative stress, 12, 14, 17
 Index 25

substances, 3, 8
Q supply, vii, 7
surgery, 11
quality of life, 13
survival, 13
Switzerland, 17
R symptoms, viii, 1, 7
syndrome, 9, 17, 19
receptors, 6, 9, 14, 18 synthesis, 8
regulation, 17
relationship, 19
T
relaxation, 3
remodeling, 7
T-cell, vii, 5
resistance, 13, 19
T-cells, vii, 5
restenosis, 11, 18
TFG, 5
revascularization, 11, 19
TGF, 6, 9
risk, viii, 12, 13, 14, 15, 18
therapeutic, viii, 11, 19
risk factors, viii, 12, 13, 15, 18
therapy, 17
thrombin, 9, 14
S thrombomodulin, 17
thrombosis, 9, 18
scavenger, 5 thromboxane, 3
search, 15 thrombus, viii, 9, 13
secrete, 5, 6, 9 tissue, 13
sedentary, vii, 1, 14 tissue plasminogen activator, 13
sedentary lifestyle, 14 TNF, 5
serotonin, 9 TNF-α, 5
services, iv toxic, 6, 14
sex, vii, 1 toxic effect, 6, 14
shoulders, 8 toxins, vii, 3
signaling, 1, 9, 11, 15 transforming growth factor, 5
signaling pathway, 1, 9, 11, 15 triggers, 1, 9
signaling pathways, 1, 9, 11, 15 tumor, 5
sites, 8 tumor necrosis factor, 5
smoking, vii, viii, 1, 3, 12, 14 turbulent, 3
smooth muscle, vii, 6, 7, 13
smooth muscle cells, vii, 6, 7
U
society, 15
stability, 8
ubiquitin, 17
stable angina, viii, 7
unstable angina, 7, 8, 9, 19
statins, 14
stenosis, 7, 11
stent, 11 V
stimulant, 13
stress, 1, 5, 12, 14, 17 variation, 18
structural changes, 1 vascular, vii, 3, 5, 13, 18
26 Index

vascular cell adhesion molecule (VCAM), vii,

5, 18
W
vascular disease, 13
World Health Organization, 17
vasoconstriction, 3, 6, 13
vasodilatation, 3
vein, 17