Interrelationships Between Cerebral Infarction
And Carotid Atherosclerosis
With Some Risk Factors
A thesis submitted to the College of Medicine, University of Al-Mustansiriya
in partial fulfilment for the requirements of the degree of
Doctor in Philosophy in Physiology
By
Basim M.H. Zwain
B.D.S. (Bag), M.Sc. (Kufa)
Supervised by
Professor Dr.
Bassam T.MF. Al-Gailani
M.B.Ch.B.(Bag)
Ph.D.(Leeds, UK)
and
Professor Dr.
Yesar MH. Al-Shamma’a
M.B.Ch.B.(Bag)
Ph.D.(Leeds, UK)
START
Supervisor
Professor Doctor Bassam T.MF. Al-Gailani
M.B.Ch.B. (Baghdad), Ph.D. (Leeds, UK).
Head Department of Physiology College of Medicine
University of Al-Mustansiriya
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Supervisor
Professor Doctor Yesar M.H. Al-Shamma’a
M.B.Ch.B. (Baghdad), Ph.D. (Leeds, UK).
Head Department of Physiology College of Medicine
University of Kufa
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Student
Basim M.H. Zwain
B.D.S. (Baghdad)
M.Sc. Physiology (Kufa)
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ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ACKNOWLEDGEMENT
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LIST OF FIGURES
LIST OF ABBREVIATIONS
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DEDICATION
To my roots and branches:
my parents,
my brothers and sisters,
my sweetheart babies
and my life partners;
my tiny effort is dedicated.
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ACKNOWLEDGEMENT
This work has been accomplished under the supervision of Professor Dr.
Bassam T. MF. Al-Gailani, Head Department of Physiology, College of
Medicine, University of Al-Mustansiriya and Professor Dr. Yesar MH. AlShamma'a, Head Department of Physiology, College of Medicine, University of
Kufa to whom I am deeply indebted for their precious advices, close guidance
and invaluable comments and remarks.
I wish to express my deep hearted gratitude and sincere thanks to the
Medical staff and sub staff in the Teaching Hospital in Najaf particularly, in
the Department of Radiology for their wonderful cooperation during the period
of work.
My deep gratitude is due to my brother Oday for his assistance in computer
aids.
I owe my family who faced the over deal of my prolonged work with patience
and sympathy to keep me always satisfied, happy and ambitious.
My appreciation is extended to all who backed me morally and materially
during my study.
My special thanks are due to the College of Medicine, University of AlMustansiriya and the College of Medicine, University of Kufa to provide me the
chance of this study.
B
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Our last prey is "Deo Gratias".
ABSTRACT
A total number of 362 subjects (of them, 184 males and 178 females) had accomplished
the full requirements of present research which included cerebral magnetic resonance
imaging (MRI), common and internal carotid Doppler ultrasonography, dental and
periodontal examinations, clinical examinations and laboratory investigations and some
information regarding gender, age, smoking and aspirin intake.
Cerebral MRI was done to know the presence or absence of cerebral infarction (CI) no
matter where, how many or how large the infarct lesions were within the brain tissues.
Doppler ultrasonography was done to measure the intima-media thickness (IMT) and to
record some of its characteristics in the right and left common and internal carotid arteries
(CCA and ICA respectively). The studied characteristics were the degree of stenosis, plaque
surface and plaque texture with the thickest intima-media and the worse characteristic to be
selected.
Dental and periodontal examinations involved inspection of the remaining dentition to
calculate the number of missing teeth (number of tooth loss) and periodontal probing to
calculate the periodontal index (PI) which represents the average loss of gingival
attachments as a measure of deterioration of periodontal status.
Clinical examinations and laboratory investigations involved measurements of systolic
and diastolic blood pressure, fasting blood sugar, serum creatinine, lipid profile "namely,
low density lipoproteins, high density lipoproteins, triglyceride and total cholesterol (LDL,
HDL, TG and TC respectively)" and specialists' reports for hypothyroid patients.
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Participants were classified into five study groups; control (those subjects who were
not belong to any of the other four groups), diabetic, hypertensive, hyperlipidemic and
hypothyroid groups. In control group, significantly strong relations were found between
IMT and age, LDL, HDL, TG, TC, PI and number of tooth loss in non-smokers, but not in
smokers.
After adjustments for age, in control group, IMT was significantly higher in smokers than in
non-smokers. IMT was significantly higher in the other study groups, with the exception of
hyperlipidemic group, than in control group.
The age of subjects with CI was found to be significantly higher than the age of those
without CI. Percentages of cerebral infarction (CI%) were significantly higher in smokers
and aspirin users. Percentages of CI were also higher in diabetic, hypertensive and
hyperlipidemic groups than in control group. No significant differences in IMT between
subjects with CI and those without CI, but significantly higher CI% was found in upper
than in lower degree of stenosis and in irregular than in smooth plaque surfaces.
The other comparisons regarding gender, serum creatinine, were not significant and. It is
suggested that age, smoking, plasma lipid concentrations, diabetes mellitus, hypertension,
hyperlipidemia and aspirin intake were strongly related risk factors for IMT and CI and
that CI is strongly related to the worse IMT characteristics of carotid artery rather than to
the overall increase in IMT. Further comprehensive researches are suggested to avoid the
impact of small population size on the unexplained outcomes.
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LIST OF CONTENTS
Item
Content
Page
DEDICATION
……………………………………………………………………………
.…
v
ACKNOWLEDGEMENT
…………………………………………………………………
.
vi
ABSTRACT…………………………………………………………………………………
..
vii
LIST OF CONTENTS
………………………………
………………………………………
..
ix
LIST OF TABLES
……………………………………………
.………………………………
xii
LIST OF FIGURES
……………………………………………
.……………………………
xiii
LIST OF ABBREVIATIONS
………………………………………………………………
.
xv
CHAPTER ONE
Introduction…………………………………………………………………………………
..
1
1.1.
Arterial diseases
……………………………………………………………………………… 1
1.1.1.
Arteriosclerosis
………………………………………………………………………………
.
1
1.1.2.
Atherosclerosis…………………………………………………………………………
.…...
2
1.1.3.
Pathogenesis…………………………………………………
.........................................
4
1.1.3.1.
Endothelial injury
…………………………………………………………………………… 5
1.1.3.2.
Hyperlipidemia………………………………………………
........................................
1.1.3.3.
Cellular interactions
………………………………………………………………………… 7
1.1.3.4.
Smooth muscle cells proliferation and extracellular matrix depos
ition……….. ………
6
8
1.1.4.
Classification of human atherosclerotic lesions
…………………………………………
...
9
1.2.
Infarction…………………………………
…………………………………………………
..
10
1.2.1
Cerebral infarction…………………………………
………………………………………
..
10
1.2.2.
Carotid atherosclerosis and cerebral infarction
…………………………………………… 11
1.3.
Risk factors……………………………………………
...…………………………………
....
12
1.3.1.
Hyperlipidemia…………...…………………………………………………………………
..
14
1.3.2.
Hypertension…………………………………………………………………………………
..
16
1.3.3.
Smoking………………………………………………………………………………………
..
18
1.3.4.
Diabetes mellitus
……………………………………………………………………………… 21
1.3.5.
Age……………………………………………………………………………………………
... 24
1.3.6.
Gender…………………………………………………………………………………………
. 24
1.3.7.
Periodontitis……………………………………………………………………………………
. 25
1.3.8.
Hypothyroidism
………………………………………………………………………………
.. 26
1.3.9.
Aspirin intake…………………………………………………………………………………
. 26
1.3.10.
Alcohol consumption
…………………………………………………………………………
.
27
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Item
Contents
Page
1.3.11.
Other risk factors
………………………………………………………………………
..
28
1.4.
Aims of thesis…………………………………………………………………………… 30
CHAPTER TWO
Subjects and methods
…………………………………………………………………
..
31
2.1.
Cerebral Magnetic Resonance Image (MRI)
…………………………………………
..
32
2.2.
Common and internal carotid Doppler ultrasonography
……………………………
.
33
2.2.1.
Measurements of Intima
-Media Thickness (IMT)
……………………………………
.
33
2.2.2.
Examination of plaque characteristics
………………………………………………… 33
2.2.2.1.
Degree of stenosis………………………………………………………………………
..
33
2.2.2.2.
Plaque surface…………………………………………………………………………
...
34
2.2.2.3.
Plaque texture……………………………………………………………………………34
2.3.
Calculation of periodontal index and number of missing teeth
……………………
..
2.4.
Clinical and laboratory investigations
………………………………………………… 35
2.4.1.
Systolic and diastolic blood pressure
…………………………………………………
...
2.4.2.
Fasting blood sugar
……………………………………………………………………
..
36
2.4.3.
Lipid profile……………………………………………………………………………
....
36
2.4.4.
Serum creatinine…………………………………………………………………………37
2.5.
Information about age, cigarette smoking, alcohol and aspirin
………………………
.
2.5.1.
Information about age
……………………………………………………………………37
2.5.2.
Information about cigarette
smoking……………………………………………………
.
35
35
37
37
2.5.3.
Information about alcohol consumption
…………………………………………………38
2.5.4.
Information about aspirin intake
………………………………………………………
..
38
2.6.
38
Hypothyroid patients
……………………………………………………………………
..
2.7.
39
Study groups………………………………………………………………………………
2.8.
39
Data analyses………………………………………………………………………………
CHAPTER THREE
Results……………………………………………………………………………………
..
40
3.1.
Numbers of participants
…………………………………………………………………
.
40
3.2.
Intima-media thickness and some risk factors
………………………………………
....
3.2.1.
In control group…………………………………………………………………………
.
42
3.2.2.
60
In the other study groups
………………………………………………………………
..
3.2.
Cerebral infarction and some risk factors
……………………………………………
..
3.2.1.
In control group………………………………………………………………………… 66
3.2.2.
In the other study groups
………………………………………………………………
.
76
3.3.
Intima-media thickness and cerebral infarction
………………………………………
.
86
42
66
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Item
Contents
Page
CHAPTER FOUR
Discussion…………………………………………………………………………………
. 95
4.1.
Relationships between atherosclerosis and cerebral infarction
thwi
some oftheirrisk
factors………………………………………………………………………………
95
4.1.1.
Gender……………………………………………………………………………………95
4.1.2.
Age………………………………………………………………………………………
..
96
4.1.3.
Smoking…………………………………………………………………………………
..
97
4.1.4.
Diabetes mellitus………………………………………………………………………
..…
4.1.5.
Hypertension……………………………………………………………………………
...
100
4.1.6.
Hyperlipidemia
……………………………………………………………………………
.
101
4.1.7.
Hypothyroidism
…………………………………………………………………………
... 102
4.1.8.
Serum creatinine
…………………………………………………………………………
.
102
99
4.1.9.
Aspirin……………………………………………………………………………………
.. 103
4.1.10.
Periodontitis and tooth loss
……………………………………………………………
.… 104
4.2.
Carotid intima-media thickness and cerebral infarction
……………………………… 106
4.3.
109
Conclusions………………………………………………………………………………
.
4.4.
110
Recommendations
………………………………………………………………………
..
REFERENCES…………………………………………………………………………
..
111
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LIST OF TABLES
Table
Title
Page
1
Number of subjects in various groups & subgroups
……………….
41
2
IMT in control group …………………………………………………
54
3
Relationships between IMT & smoking in the five age groups
……
55
4
Relationships between IMT & smoking in the five study groups
…..
65
5
Percentage of CI in control group……………………………………
.
67
6
Relationships between CI% & smoking in the five age groups
……..
72
7
Relationships between CI% & smoking in the five study groups
…..
85
8
Percentage of CI with various plaque characteristics
………………..
88
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LIST OF FIGURES
Figure
Title
Page
1a
Regression of IMT on age in control smokers & non-smokers
without CI……………………………………………………….
43
Regression of IMT on age in control smokers & non-smokers
without CI after omitting three of the dispersed data series....
44
Regression of plasma lipid concentrations on IMT in control
non-smokers without CI……………………………………
46
Regression of plasma lipid concentrations on age in control
non-smokers without CI………………………………………
47
Regression of plasma lipid concentrations on IMT in control
smokers without CI…………………………………………
48
Regression of plasma lipid concentrations on age in control
smokers without CI…………………………………………..
49
6
Regression of IMT on tooth loss in control group…………..
51
7
Regression of IMT on periodontal index in control group…..
52
8
IMT in control non-smokers & smokers…………………….
56
9
IMT in control non-smokers & smokers after age matching
57
10
IMT in control YES & NO aspirin groups after age matching
59
11
IMT in non-smoker control & diabetic groups after age
matching………………………………………………………..
61
IMT in non-smoker control & hypertensive groups after age
matching …………………………………………………………
62
IMT in non-smoker control & hyperlipidemic groups after age
matching …………………………………………………….
63
IMT in non-smoker control & hypothyroid groups after age
matching……………………………………………………….…
64
Percentage of CI in control YES & NO aspirin groups after
age matching…………………………………………………….
68
Percentage of CI in control males & females taking no aspirin
69
1b
2
3
4
5
12
13
14
15
16
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Figure
17
Title
Page
Percentage of CI in control non- smokers & smokers taking no
aspirin ………………………………………………………
70
Percentage of CI in control non- smokers & smokers after age
matching ………………….. ……………………………….…
71
19
Number of tooth loss in control groups with & without CI
……
74
20
Periodontal index in control groups with & without
CI……...…..
75
18
21
Percentage of CI in non- smoker control & diabetic groups after
age matching …………………………………………………
.. 77
22
Percentage of CI in non- smoker control & hypertensive groups
after age matching ……………………………………………
78
Percentage of CI in non- smoker control & hyperlipidemic
groups after age matching….. ……………………………….
79
Percentage of CI in non- smoker control & hypothyroid groups
after age matching …………………………………………..
80
23
24
25
Percentage of CI in non- smoker control & diabetic groups
taking no aspirin ……………………………………………… 81
26
Percentage of CI in non- smoker control & hypertensive groups
taking no aspirin ……………………………………………..
82
Percentage of CI in non- smoker control & hyperlipidemic
groups taking no aspirin ……………………………………..
83
27
28
Percentage of CI in non- smoker control & hypothyroid groups
taking no aspirin ………………………………………………
. 84
29
IMT in control groups with & without CI after age matching
…
87
30
Percentage of CI in low & up degrees of stenosis after age
matching ………………………………………………………
89
31
Percentage of CI in smooth & irregular plaque surface after age
matching ………………………………………………………
. 90
32
Percentage of CI in homogenous & heterogeneous plaque
texture after age matching …………………………………..
91
33
IMT in smooth & irregular plaque surface after age matching.. 93
34
IMT in homogenous & heterogeneous plaque texture after age
matching ………………………………………………………
..
B
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LIST OF ABBREVIATIONS
Abbreviation
Its meaning
CCA
=Common carotid artery
CI
=Cerebral infarction
CI%
=Percentage of cerebral infarction
CR
=Control group
CRT
=Serum creatinine
CS
=Current smokers
DBP
=Diastolic blood pressure
DM
=Diabetic group
FBS
=Fasting blood sugar
HDL
=High density lipoproteins
Hetero
=Heterogeneous plaque texture
HL
=Hyperlipidemic group
HO
=Hypothyroid group
Homo
=Homogenous plaque texture
HT
=Hypertensive group
ICA
=Internal carotid artery
IMT
=Intima media thickness
Irregular
=Markedly irregular to ulcerated plaque surface
LDL
=Low density lipoproteins
LOW
=Less than 50% degree of stenosis
MRI
=Magnetic resonance image
NO
=Not taking aspirin
NS
=Non-smokers
SBP
=Systolic blood pressure
Smooth
=Smooth to mildly irregular plaque surface
TC
=Total cholesterol
TG
=Triglycerides
UP
=Equal to or more than 50% degree of stenosis
YES
=Taking aspirin
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CHAPTER ONE
Introduction
1. 1. Arterial diseases:
Vascular disorders are responsible for more morbidity and mortality than any other
category of human disease (Schettler et al 1978). Among them, arterial diseases are the
most important (Strong et al 1978). They achieve this unenviable preeminence by:
Narrowing vessels and thus producing ischemia of tissues perfused by such vessels (Glagov
1988).
Damaging the endothelial lining and thus promoting intravascular thrombosis, a process
that contributes to critical ischemia of vital organs such as the heart and brain (Cotran
1987).
Weakening the walls of vessels, predisposing to dilation or possibly rupture (Kashgarian
1985).
Contributing to the pathogenesis of some of the most common diseases in human, namely,
atherosclerosis, hypertension and diabetes (McSween and Whaley 1992).
Although disorders of veins are by no means trivial; they are dwarfed in significance by
the diseases of arteries, in particular atherosclerosis (Dawber 1980).
1. 1. 1. Arteriosclerosis:
Arteriosclerosis is the generic name for three patterns of vascular disease, all of which
cause thickening and inelasticity of arteries (Majno et al 1985). These three patterns are:
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.The dominant form is atherosclerosis, characterized by the formation of intimal fibrofatty 
plaques that often have a central grumous core rich in lipid, hence the Greek stem athera,
meaning "gruel or porridge" and sclerosis, meaning "scarring" (Bocan et al 1986).
.The second morphologic form of arteriosclerosis is the rather trivial Mönckeberg's medial
calcific sclerosis, characterized by calcifications in the media of medium-sized muscular
arteries in persons older than 50 years. The calcifications take the form of irregular medial
plates or discrete transverse rings; they create nodularity on palpation and are readily
visualized radiographically. Occasionally the calcific deposits undergo ossification. Since
these medial lesions do not encroach on the vessel lumen, medial calcific sclerosis is largely
of anatomic interest alone; however, arteries so affected may also develop atherosclerosis
(Neufeld and Blieden 1978).
.The third pattern is arteriosclerosis of small arteries and arterioles. Small vessel sclerosis is
most often associated with hypertension and diabetes mellitus. There are two anatomic
variants, hyaline and hyperplastic, depending on the cause and rate of progression of
disease (Gamble 1986).
1. 2. Atherosclerosis
No disease in the developed countries is responsible for more deaths, has stimulated more
research and has engendered more controversy about how best to control it than
atherosclerosis (Schettler et al 1978). Atherosclerosis alone accounts for more than half of
all deaths in the Western World (McGill 1968.I). Basically, it is characterized by intimal
plaques called atheromas that protrude into the lumen, weaken the underlying media and
undergo a series of complications (Haust 1978).
R B E H
Atherothrombotic disease of the cerebral vessels is the major cause of cerebral infarction or
stroke; one of the most common forms of neurologic disease (Garcia 1985). Although any
artery may be affected, the major targets of atherosclerosis are the aorta and the coronary
and cerebral arteries (McGill 1968.F), but carotid atherosclerosis had been found to be an
indicator of generalized atherosclerosis (Grobbee and Bots1994).
The disease begins in early childhood and progresses slowly over the decades (McGill et
al 1963). Thus, in some sense atherosclerosis is a pediatric disease, and if its toll is to be
reduced, measures must be instituted early before it rears its ugly head and provokes one of
its unfortunate consequences (Strong 1978). Atherosclerosis is much less prevalent in
Central and South America, Africa, Asia and the Orient than in North America, Europe,
Australia and New Zealand (McGill 1968.I).
Successful efforts to bring atherosclerosis under control were undertaken including
reduced cigarette smoking, altered dietary habits with reduced consumption of cholesterol
and other saturated animal fats, better control of hypertension, and improved methods of
treatment of nonfatal myocardial infarcts and even vaccination (Kannel and Thom 1984,
Buring and Hennekens 1994, Verschuren et al 2005, Nilsson et al 2005 and Kawakami 2005).
Atherosclerosis is as old as man (McGill et al 1963). Ruffer in 1910 studied Egyptian
mummies at the medical school in Cairo and found aortic atherosclerosis just as it occurs in
Egyptians of today.
The word atheroma or "porridge-tumor" was first used in the ancient Greek literature
to describe any cystic space containing gruel-like material. It was introduced by Von Haller
in 1755 to denote the common type of plaque which on sectioning exudes its yellow
pultaceous contents.
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Lobstein in 1833 used the word "arteriosclerosis" a term today is applied to any hardening
of vessels. Virchow in 1862, observed cellular components in many plaques which
suggested to him that they were inflammatory in origin; he described the lesions as
"endarteritis deformans nodosa". Marchand in his study of "fatty degeneration of the
intima" said: As long as the proper overgrowth of connective tissue is absent; it is more
correct not to talk of arteriosclerosis but of simple atheroma (Marchand 1904).
Marchand introduced the term so popular today; atherosclerosis. He did not intend it to
be a specific name for any one form of lesion, but meant it to include all diseases of all
arterial coats, and to emphasize the importance of fatty elements.
The definition given by the World Health Organization 1958 suggested that it should be
applied to plaques in which, though fatty softening is predominant; variable
combination of changes occur consisting of focal accumulation of lipids, complex
carbohydrates, blood and blood products, fibrous tissue and calcium deposits. Atheroma
is primarily a lipid deposition in the intimal lining of blood vessels. It is almost certain
that mural platelets and fibrin deposition come to overlie the lipid deposit, as it happens
with any imperfection of the endothelial lining (Ross 1986). In the later stages, fibrosis,
calcification, ulceration and thrombosis occur as common complications of the lesion
(Kumar et al 1997).
1. 3. Pathogenesis:
Understandably, the commanding importance of atherosclerosis has stimulated
enormous efforts to discover its cause, and a number of hypotheses for its pathogenesis
have been proposed (Munro and Cotran 1988, Cunningham and Pasternak 1988,
Tybjærg-Hansen et al 2005 and Seidelmann et al 2005).
R B E H
The currently favored theory and the one receiving the greatest attention is the response-toinjury hypothesis (Wissler 1980). It best accommodates the various risk factors. Central
to this hypothesis are the following features:
Endothelial injury: The development of focal areas of chronic endothelial injury, usually
subtle, with resulting increase endothelial permeability or other evidence of endothelial
dysfunction (Cotran 1987 and Glasser et al 1996).
Hyperlipidemia: Increased insudation of lipoproteins into the vessel wall, mainly low
density lipoprotein (LDL) or modified LDL with its high cholesterol content and also
very low density lipoprotein (Goldstein and Brown 1977).
Cellular interactions: A series of cellular interactions in these foci of injury involving
endothelial cells, monocytes, macrophages, T-lymphocytes and smooth muscle cells of
intimal or medial origin (Bendit 1978).
Proliferation of smooth muscle cells in the intima with formation of extracellular matrix
(Haust 1960 and Geer et al 1972).
1. 1. 3. 1. Endothelial injury:
Chronic or repeated endothelial injury is the cornerstone of the response-to-injury
hypothesis (Cotran 1987). Although endothelial denuding injuries certainly initiates
R
atherosclerotic changes in experimental animals; the naturally occurring disease of
humans begins with some form of nondenuding subtle injury. Circulating endotoxins,
B
hypoxia products derived from cigarette smoke, viruses and specific endothelial toxins
such as homocysteine (accounting for the premature and severe atherosclerosis
E
homocystinurics) could be involved, but thought to be much likely are hemodynamic
disturbances (shear stress, turbulent flow) and adverse effects of hypercholesterolemia, perhaps
H
acting in concert. Shear stress and turbulent flow cause increased endothelial permeability and cell
turnover, enhanced receptor-mediated LDL endocytosis and increased endothelial adhesivity to
leukocytes. These alterations are concomitant with altered gene expression of important molecules,
such as cytokines, adhesion molecules and coagulation proteins. The complex geometry of the
arterial system with its twists and turns and branching, could give rise to turbulent flow patterns
with variable levels of shear stress capable of causing focal areas of such endothelial dysfunction. In
support of this notion is a well defined tendency for plaques to occur at mouths of exiting vessels,
branch points and along the posterior wall of the descending and abdominal aorta which is caught
between the "anvil" of the vertebral column and the "hammer" of the arterial pulse (Gimbrone
1980).
1. 3. 2. Hyperlipidemia:
Chronic hyperlipidemia contributes to atherogenesis in several ways. It may itself initiate
endothelial dysfunction and/or the accumulation of lipoproteins within the intima at sites of
endothelial injury or dysfunction. Most important, it provides the opportunity for modification of
lipid in the arterial wall, largely by oxidative mechanisms, yielding modified LDL. Oxidative
modification of LDL is currently thought to be a significant aspect of atherogenic proces (GómezMuñoz et al 2000). It is proposed that LDL in the microenvironment of interadherent monocytes
and endothelial cells is exposed to free radicals generated by these activated cells. Oxidized LDL
contributes to atherogenesis in the following ways (Gotto 1979):
1. It is readily ingested by macrophages through the scavenger receptor that is distinct from the LDL
receptor.
2. It is chemotactic for circulating monocytes.
3. It increases monocytes adhesion.
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4. It inhibits the motility of macrophages already in lesions thus favoring the recruitment
and retention of macrophages in the lesions.
5. It stimulates release of growth factors and cytokines.
6. It is cytotoxic to endothelial and smooth muscle cells.
7. It is immunogenic.
1. 1. 3. 3. Cellular interactions:
A complex series of cellular events similar to those that occur in chronic inflammation are
involved in the formation of atheromatous plaques. After some form of endothelial injury
monocytes adhere and migrate between endothelial cells to localize subendothelially. There
they become transformed into macrophages and avidly engulf lipoproteins (Brown and
Goldstein 1983), largely oxidized LDL to become foam cells. Recall the oxidized LDL is
chemotactic to monocytes and immobilizes macrophages at sites where it accumulates
(Gerrity 1981).
Macrophages also proliferate in the intima (Bradley and Tontonoz 2005). If the injury is
denuding, platelets also adhere to the endothelium. Early in the evolution of the lesion,
smooth muscle cells some of medial origin migrate and gather in the intima, where they
proliferate and some take up lipids to also be transformed into foam cells. As long as the
hypercholesterolemia persists, monocytes adhesion, subendothelial migration of smooth
muscle cells and accumulation of lipids within the macrophages and smooth muscle cells
continue, eventually yielding aggregates of foam cells in the intima which are apparent
macroscopically as fatty streaks. These, many believe, are the forerunners of the fully
evolved atheromas. Should the disease be ameliorated, these fatty streaks may regress, but if
they persist; they continue to evolve (Kissane 1990).
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1. 1. 3. 4. Smooth muscle cells proliferation and extracellular matrix deposition:
Finally, growth stimulators and growth inhibitors elaborated by macrophages may
modulate the proliferation of smooth muscle cells and the deposition of extracellular matrix
in the lesion (Bierman and Albers 1975). T-lymphocytes are also present in atheromas, but
the precise stimuli for their recruitment and their roles in the evolution of atheromas are
uncertain. Proliferation of smooth muscle cells about the focus of foam cells converts the
fatty streaks into a mature fibrofatty atheroma. Arterial smooth muscle cells can synthesize
collagen, elastin and glycoproteins.
A number of growth factors have been implicated in the proliferation of smooth muscle
cells, most importantly Platelet-derived growth factor (PDGF), which is released from
platelets adherent to the focus of endothelial injury (Grotendorst et al 1982) but is also
produced by macrophages, endothelial cells and smooth muscle cells. Additional candidate
mitogens are fibroblast growth factor (FGF) and transforming growth factor-α (TGF- α).
Indeed, the evolving atheroma has been likened to a chronic inflammatory reaction, with
activated T-cells, monocytes /macrophages, endothelial cells and smooth muscle cells all
expressing or contributing a variety of cytokines that could play roles in cell adhesion
locomotion and replication. A variety of growth inhibitors modulate smooth muscle cell
proliferation. These include heparin-like molecules, present in endothelial cells and smooth
muscle cells or the transforming growth factor-β (TGF-β), derived from endothelial cells or
macrophages. At this stage in atherogenesis, the intimal plaque represents a central
aggregation of foam cells of macrophages and smooth muscle cell origin, some of which may
have died and released extracellular lipid and cellular debris surrounded by smooth muscle
cells. With progression, the cellular fatty atheroma is modified by further deposition of
collagen, elastin and proteoglycans. This connective tissue
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is particularly prominent on the intimal aspect, where it produces the so called fibrous cap.
Thus evolves the fully mature fibrofatty atheroma. Some atheromas undergo considerable
cellular proliferation and connective tissue formation to yield fibrous plaques. Others retain
a central core of lipid-laden cells and fatty debris. Thrombosis is a complication of late stage
atherosclerosis and organization of thrombi may contribute to plaque formation and their
encroachment on the lumen. Platelets generally do not adhere to the arterial wall without
prior severe injury or endothelial denudation; more subtle biochemical disruptions of a
normal endothelial cell could render it thrombogenic (Haust 1960).
1. 1. 4. Classification of human atherosclerotic lesions:
The American Heart Association classified human atherosclerotic lesions as follows
(Stary 1992):
Type I. (Initial or fatty dot lesion): isolated macrophage foam cells.
Type II. (Fatty streak lesion): mainly intracellular lipid accumulation.
Type III. (Intermediate lesion): type II + small extracellular lipid pool.
Type IV. (Atheroma lesion): type II + core of extracellular lipid.
Type V. (Fibroatheroma lesion): lipid core and fibrotic layer, or multiple lipid cores and
fibrotic layers, or mainly calcific, or mainly fibrotic.
Type VI. (Complicated lesion): surface defect, hematoma-hemorrhage, thrombus.
Type IV may also progress directly into type VI. Growth of types I, II, III and IV is
mainly by lipid accumulation while type V by accelerated smooth muscle and collagen
increase and type VI by thrombosis and hematoma. The earliest onset of types I and II is
from first decade of life, types III and IV from third decade and types V and VI from fourth
decade. Types I, II and III are clinically silent while types IV, V and VI are silent or overt
(Stary 1992).
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1. 2. Infarction:
Tissue necrosis due to reduction or loss of blood supply is termed infarction. An infarct is
usually due to obstruction of one or more arteries by thrombosis or embolism. Occasionally,
the blood flow may be stopped by occlusion of the draining veins and venous infarction may
then occur. The term infarction, literally translated, means "stuffing in" and was originally
applied to infarcts in tissues in which good collateral circulation caused hemorrhage into the
dying tissue. In most tissues an established infarct appears pale. The size of an infarct
depends upon the amount of tissue rendered ischemic, the severity and duration of the
ischemia and the susceptibility of the tissue cells to ischemia. Infarcts may be red or pale
and may undergo coagulative or colliquative necrosis. Since hypoxic cells cannot maintain
ionic gradients, they absorb water and swell. Recent infarcts are therefore raised above the
surface of the organ; the swelling of a large cerebral infarction may cause a fatal increase in
intracranial pressure because the brain is confined by the skull. In the days following
infarction, the products of the dead cells diffuse out and promote an acute inflammatory
reaction at the margin, with vascular congestion, edema and migration of polymorphs and
macrophages into the dead tissue (Kissane 1990).
2. 1. Cerebral infarction:
The cerebral infarcts may be pale or hemorrhagic with colliquative necrosis (Tuszynski
et al 1989) and the neural tissue breaks down to form a soft pulpy mass. The debris is
gradually removed by macrophages which become bloated with myelin. The residual cavity,
once termed an "apoplectic cyst" eventually contains clear fluid and is walled off by gliosis
(Schochet 1983). In localized pyogenic infections, toxic injury to the endothelium of veins
involved in the lesion may result in thrombosis. Bacteria may invade and multiply in the
thrombus, which then becomes
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heavily infiltrated by neutrophils and broken down by their digestive enzymes. Small
fragments of the softened septic thrombus may then break away and be carried off in the
blood (pyemia or pus in the blood), where they become impacted in small vessels. They
cause local injury both by obstructing the vessels and by the release of toxins from their
contained bacteria. A combination of necrosis, hemorrhage and suppuration results, with
formation of multiple pyemic abscesses in the various tissues, their distribution depending
on the site of the original septic thrombosis. Fragments of infected thrombi released into the
circulation may impact in arteries causing correspondingly larger foci of necrosis and
suppuration "septic infarcts" (Schochet 1983). Cerebral infarction was found to be
associated with cardiovascular disorders (Feinberg et al 1990, Tanaka et al 1993, Ezekowitz
et al 1995 and Schoen and Gimbrone 1996) particularly atherosclerosis (Chambless et al
2000).
1. 2. 2. Carotid atherosclerosis and cerebral infarction:
The Intima-media Thickness (IMT) of the carotid artery, as measured by B-mode
ultrasound, is a measure of preclinical atherosclerosis that has been shown to be associated
with incident stroke (O'Leary et al. 1999 and Chambless et al 2000) and namely cerebral
infarction (Macko et al 1996). The IMT of both internal carotid artery (ICA) and common
carotid artery (CCA) had been linked to coronary heart disease and to atherosclerotic
disease in other vascular beds. This association is found to be stronger for ICA than for
CCA (O'Leary et al 1996). A lesser but still significant association was observed with mild
degrees of carotid stenosis (O'Leary et al 1992). Polak et al found IMT of internal carotid
artery to be strongly associated with clinical manifestations of cerebrovascular disease
(Polak et al 1993).
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In a multivariate regression analysis that included several risk factors and measures of
cardiovascular diseases (CVD), they found IMT of internal carotid artery to be the best
predictor of transient ischemic attack (TIA) and stroke. The association seen between IMT
of internal carotid artery and Magnetic Resonance Image (MRI) infarcts in TIA subjects in
this study further indicates that the association also applies to morphological brain changes.
Whether their presence suggests an increased risk for incident stroke is a matter that needs
to be addressed in the future by long-term follow-up studies (Polak et al 1993). Cerebral
lesions are generally considered to be the consequences of atherosclerosis, arteriosclerosis,
cerebral hypoperfusion, or ischemia (Awad et al 1986, van Swieten et al 1991, Forsting et al
1991, Meyer et al 1992 and Price et al 1997). These cerebral lesions may be the precursors of
clinical stroke (Forsting et al 1991, van Swieten et al 1991, Breteler et al 1994, Liao et al
1997 and Price et al 1997).
1. 3. Risk factors:
Atherosclerosis is a disease of the old age group, although it has been reported in infants
on rare occasions (Strong et al 1978). It is much commoner in men than in women up to the
age of menopause; after that, the incidence tends to be at the same level in both sexes
(Dawber 1980). Patients with high blood cholesterol tend to develop atheroma at an
earlier age and to a more severe degree than do healthy subjects as in diabetes mellitus,
myxedema, nephrosis and xanthomatosis (Stamler 1978). This is an independent risk factor,
but there are some other risk factors that accelerate the process of atherosclerosis especially
when lipid abnormality is also present which are called the additive risk factors. These are
age (Salonen and Salonen 1991), male sex (O'Leary et al 1991), hypertension (Psaty et all
1992.I and Bots et al 1993), and its medication (Psaty et al 1992.A and Thrift et al 1996),
diabetes mellitus
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(Bonithon-Kopp et al 1991 and Golden et al 2002), severe obesity (Abbott et al 1987,
Blankenhorn et al 1993, Furberg et al 1994 and Crouse et al 1995), cigarette smoking (Hays
et al 1996 and Villablanca et al 2000), alcohol consumption (Ding et al 2004), periodontitis
(Beck et al 2001) and hypothyroidism (Hak et al.2000).
Several studies have shown that hypertension, hyperlipidemia, male sex, age, smoking,
and postmenopausal status are consistent and independent factors that contribute to
increasing carotid IMT (Heiss et al 1991, O'Leary et al 1992 and Wagenknecht et al 1997).
The prevalence and severity of the disease and therefore the age when it is likely to cause
tissue or organ injury are related to a number of factors, some constitutional and therefore
immutable, but others acquired and potentially controllable. The constitutional factors
include age, sex and familial background (Stamler 1978).
There are four major acquired risk factors that are at least in some part amenable to
control. They are hyperlipidemia, hypertension, diabetes mellitus and cigarette smoking. In
addition there are a number of less important "soft" risks. These minor factors are
associated with a less pronounced and difficult-to-quantitate risk. These include insufficient
regular physical activity, competitive stressful life style, obesity, oral contraceptives,
hyperuricemia, high carbohydrate intake and hyperhomocysteinemia (Stamler 1978).
Multiple factors had been shown to impose more than additive effect. When three risk
factors are present, e.g., hyperlipidemia, hypertension and smoking, the heart attack rate is
seven greater than when none are present. Two risk factors increase the risk fourfold.
However, the converse is equally important i.e., atherosclerosis may develop in absence of
any apparent risk factors (McSween and Whaley 1992).
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1. 3. 1. Hyperlipidemia:
Hyperlipidemia is universally acknowledged to be a major factor for atherosclerosis (Oalmann et al
1981). Most of the evidence implicates hypercholesterolemia (Haust 1978), but hypertriglyceridemia
may also play a role, although it is not as significant as hypercholesterolemia (Gotto 1979). The major
evidence implicating hypercholesterolemia in the genesis of atherosclerosis includes the following:
High cholesterol diets can produce Atherosclerotic plaques in experimental animals, including
nonhuman primates, which are nearly identical to those, observed in human disease (Verschuren et al
2005).
The major lipids in atheromas (plaques) are cholesterol and cholesteryl esters derived from the
plasma (Grundy et al 2004).
Many large-scale epidemiological analyses have demonstrated a significant correlation between the
total plasma cholesterol or LDL level and the severity of atherosclerosis as judged by the mortality rate
from ischemic heart disease (Boon et al 1994). The higher the total cholesterol level, the greater the
symptomatic and fatal atherosclerotic disease. No threshold clearly separates persons at risk from those
free of risk, but in general, atherosclerotic events are very uncommon with total cholesterol levels below
150 mg/dl. Hypertriglyceridemia, as manifested by elevated very low density lipoproteins (VLDL)
levels, is also associated with some increased risk (McSween and Whaley 1992).
Genetic or acquired disorders (e.g., familial hypercholesterolemia, diabetes mellitus and
Hypothyroidism) that cause hypercholesterolemia lead to premature and severe atherosclerosis; an
example is familial hypercholesterolemia, which in the homozygous state is often associated with
myocardial infarction before age 20 years (Wendelhag et al 1992).
When levels of serum cholesterol are lowered by diet or drugs (Blankenhorn et al 1993 and Chen and
Farese 2004), there is evidence in animals that some of atherosclerotic plaques regress, or fail to
progress within months and that the risk of cardiovascular mortality in selected patients is reduced.
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Genetic manipulations of lipid components in mice (e.g. apolipoprotein E deficiency) lead to
abnormal lipid metabolism and atheromatous lesions in these animals (McSween and
Whaley 1992). It was also found that apolipoprotein E promotes the regression of
atherosclerosis independently of lowering plasma cholesterol levels (Raffai et al 2005).
The essential factor associated with development of atherosclerosis is elevated serum
total cholesterol or low density lipoproteins (LDL), low high density lipoproteins (HDL) or
both (Wendelhag et al 1992). High density lipoproteins and were found to be protective
against stroke, whereas lipoprotein-a increased the risk (Jeng et al 1999 and Sacco et al
2001).
When other potential factors are taken into account, including hypertension, diabetes,
coronary heart disease (CHD), smoking, body mass and socio-economic factors (education);
individuals with elevated HDL levels benefited from a reduction in the risk for stroke.
People with HDL in the range of 35–50mg/dl demonstrated a lower risk. This protective
effect was even greater in those with a HDL above 50 mg/dl. A 5mg/dl increase in HDL
resulted in approximately a 24% reduction in stroke risk (McSween and Whaley 1992).
If stroke is subdivided into atherosclerotic (large carotid artery disease, intracranial
atherosclerotic disease) and non-atherosclerotic (cryptogenic, lacunar and cardio-embolic
strokes) categories; the protective effect of HDL is increased still further in events of
atherosclerotic origin. Greater protection with intermediate and high HDL levels was seen
in the atherosclerotic compared with the non-atherosclerotic subgroup. This suggests that
the effect of HDL may be greater in the atherosclerotic stroke subgroup. This is in line with
the cardioprotective effect seen in coronary heart disease (Sacco 2001). It is important at
this point to emphasize the inverse relationship between symptomatic atherosclerosis and
the HDL level. High density lipoprotein
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participates in reverse transport of cholesterol and is believed to mobilize this lipid from
cells and presumably from atherosclerotic plaques and transport it to the liver for excretion
in the bile. The higher the levels of HDL, the lower are the risk of ischemic heart disease.
Hence, there is a great interest in dietary methods of lowering serum LDL and raising
serum HDL. Nondietary influences may also affect the level of blood lipids. Exercise and
moderate consumption of ethanol both raise the HDL level, whereas obesity and smoking
lower it (McSween and Whaley 1992).
3. 2. Hypertension:
The term hypertension, used without qualification, is synonymous with systemic arterial
hypertension. However, hypertension is defined as raised pressure in a vascular bed. It
affects 15-20% of population in many developed countries (Kashgarian 1985).
Blood pressure rises through childhood and adolescence and reaches the
plateau of normal adult levels in the third decade. However, mean blood pressure
continues to increase with age but there is considerable individual variation in this
increase and any diving line between normal and abnormal is arbitrary (Berglund
1989). Rough working definitions of hypertension have been laid down by the
World Health Organization as follows:
Hypertension: systolic pressure ≥160mmHg and/or diastolic pressure
≥95mmHg.
Border line hypertension: systolic pressure =140-160 mmHg and/or diastolic
pressure =90–95mmHg (McSween and Whaley 1992 and Kaplan 1997).
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In about 95% of cases of hypertension the cause is not apparent and these patients are said
to have primary, essential or idiopathic hypertension (which is either benign 90% or
malignant 10%). In the remaining 5% hypertension is secondary to other disease processes.
Benign hypertension causes changes in arteries of all sizes. In vessels from the aorta down to
the smallest arteries, the changes are widespread and are termed hypertensive
arteriosclerosis. The arteriosclerotic changes are similar to those observed in normotensive
elderly subjects (Castleman and Smithwick 1948, Kannel, Schwartz and McNamara 1969
and Berk and Alexander 1996).
In prospective studies increased blood pressure (both systolic and diastolic) has been
consistently shown to be associated with a subsequent increased risk of ischemic heart
diseases. In some community studies the risk in the 20% of the population with the highest
pressures was four times that for the 20% with the lowest pressures. The relationship
between blood pressure and ischemic heart diseases is not a simple linear one and there is
considerable clinical debate as to the levels above which the risk is increased (Braunwald
1991).
Hypertension is a major risk factor for atherosclerosis at all ages and, after age 45, may
well be more important than hypercholesterolemia (Kannel et al 1970.L).
Men age 45-62 years whose blood pressure exceeds 150/95mmHg have a more than
fivefold greater risk of IHD than those with blood pressures of 140/90mmHg or lower. Both
systolic and diastolic levels are important in increasing risk (Kannel et al 1976 and
Zanchetti 1997).
Hypertension has long been known to be a major risk factor for stroke (Kannel et al
1970, D'Agostino et al 1994 and Chanorro et al 1996) with systolic pressure appearing to be
a stronger risk factor than diastolic (Rutan et al 1988).
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Bhadelia et al in 1999, however, found that transient ischemic attack (TIA) subjects with
MRI infarcts 3 mm in maximum diameter have significantly higher diastolic blood pressure
and carotid wall IMT than TIA subjects without infarcts. This relationship was independent
of age, sex, and other risk factors. Moreover, increasing values of diastolic blood pressure
and internal carotid artery IMT were associated with higher risk of MRI infarcts in subjects
with TIA.
Association between diastolic blood pressure and brain infarcts has been demonstrated
before by imaging and autopsy studies. This relationship between diastolic blood pressure
and brain infarcts is believed to be due to hypertension-induced increase in cerebral
microvascular tone (Mast et al 1995, Shinkawa et al 1995 and Chanorro et al 1996).
3. 3. Smoking:
Endothelial dysfunction, altered lipid metabolism and adrenergic stimulation induced by
smoking can lead to vascular damage (Hays et al 1996 and Villablanca et al 2000).
Smoking is associated with increased risk for cardiovascular disease (Stamler et al 1993).
A prospective study by Kannel and his group clearly showed that smokers had a threefold
higher rate of sudden death (concerning heart disease) than did non-smokers (Kannel et al
1975). Smoking is thought to account for the relatively recent increase in the incidence
and severity of atherosclerosis in women. When one or more packs of cigarettes are smoked
per day for several years, the death rate from IHD increases up by 200%. As with serum
cholesterol and hypertension, the risk is continuous. The person smoking more has a greater
risk of having a major coronary event than a person who smokes less. Cessation of smoking
reduces this increased risk in time (Strong and Richards 1976).
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Cigarette smoking was found to be one of the major contributing factors to the pathogenesis
of atherosclerosis (McGill et al 1963). In 1962, the Albany and Farmingham studies clearly
demonstrated the definite relationship between cigarette smoking and morbidity and
mortality from myocardial infarction and death from coronary disease (Doyle et al 1962).
Other studies by Paul et al 1963 and Kannel et al 1966 added weight to the theory that
cigarettes played a major role in the formation of atherosclerosis.
A long term study by Paffenbarger et al in 1966 indicated that the smoking habits of
college students (dating back as far as 1926) were statistically related to their development
of coronary disease in later life.
In 1964, the Surgeon General's report indicated that cigarette smokers (greater than one
pack per day) had a three times greater chance of having a coronary event than nonsmokers.
Epidemiological studies, therefore, have been convincingly relating cigarette smoking to
the development of atherosclerosis. There has been equally good evidence from the autopsy
table correlating the amount of smoking and coronary atherosclerosis since when Auerbach
and his associates studied the degree of atherosclerosis in 1372 men who died of disease
other than coronary heart disease. Experienced interviewers (who were not familiar with
the autopsy findings) obtained histories from the families of these men concerning their past
smoking habits. This study showed not only that smokers have higher percentage of
coronary atherosclerosis than non-smokers, but that "within age group, the proportion of
cigarette smokers with an advanced degree of atherosclerosis increased constantly with the
amount of cigarette smoking " (Auerbach et al 1965).
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In animal experiments, nicotine has been administered in large amounts without atherogenic effects
except for the suggestion that it may cause necrosis and calcifications of the medial arterial layers
(Hammond 1966 and Kahn 1966).
Coronary arteriography studies have demonstrated a correlation between the number of cigarettes
consumed and the severity of coronary artery disease as well as the accelerating effect of cigarette
consumption on the development of coronary artery disease (Herbert 1975).
It has been though for years that nicotine causes vasoconstriction as well as increased heart rate and
blood pressure secondary to discharge of catecholamines. However, evidence from the experiments of
Cryer et al 1976 strongly suggests that the hemodynamic effects of smoking are not mediated by the
elevated plasma chatecholamines but are the result of immediate local release of norepinephrine from
sympathetic nerves innervating the heart and other tissues. This study showed that within 10 minutes of
the start of smoking there was a significant elevation of plasma norepinephrine and epinephrine. The
increase in pulse rate and blood pressure preceded the elevations of plasma catecholamines and was so
prevented by prior adrenergic blockade.
Aronow in 1976 had centered a great deal of investigation around the effects of carbon
monoxide on the cardiovascular system. It is known that smokers have CO levels of 400ppm
in their pulmonary capillary blood which causes high carboxyhemoglobin (COHb) levels
(10-18%). Aronow has also shown that since the "affinity of hemoglobin for CO is
approximately 245 times greater than its affinity for oxygen; CO displaces oxygen from
hemoglobin, reducing the amount of oxygen available to the myocardium". Carbon
monoxide causes a shift to the left of the oxygen-hemoglobin (O2- Hb) dissociation curve,
which in turn causes a tighter binding of O2 to Hb and thereby decreases the availability of
O2 to the arterial wall and myocardium (Ayres et al 1970).
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Hypoxia alone (10% O2) in cholesterol-fed rabbits produces lesions in the arterial
wall indistinguishable from those found in similarly fed rabbits with COHb levels
of 15% (Astrup et al 1968 and Kjeldsen et al 1968). The aortas, femoral and
coronary vessels all showed lipid deposition of a higher degree in the experimental
CO-exposed rabbits than the control rabbits that were fed only cholesterol; the
average content of cholesterol per 100g wet weight of aortic tissue was 703mg in
the control group and 1774mg in the CO-exposed group. Rabbits on a normal diet
and exposed to CO for 13 weeks with levels of COHb of 10%-11% developed focal
intimal and subintimal changes in a significantly higher degree than nonexposed
control animals (Astrup et al 1968).
Triggering lipid accumulation in the arterial lumen (Whereat et al 1970) and
increasing platelet stickiness (Birnstingl et al 1971) are two other biochemical
effects of carbon monoxide.
It can be concluded that cigarette smoking has a definite effect on the formation
of atherosclerosis, and more specifically, that carbon monoxide can be a major
factor in the acceleration of the atherosclerotic process.
1. 3. 4. Diabetes mellitus:
Diabetes mellitus is not a single disease but the pathological and metabolic state
caused by inadequate insulin action. A feature common to all types is glucose
intolerance. It is defined clinically as either a fasting plasma glucose level greater
than 140mg/dl or a two hour post-prandial plasma glucose greater than 200mg/dl
(McSween and Whaley 1992).
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It has been recognized for years that the main problem in diabetes mellitus is the enhanced
risk of premature atherosclerosis. This has been documented extensively by retrospective
and autopsy studies (Kissane 1990).
Insulin is a major anabolic hormone. In addition to its other functions, it promotes the
uptake of free fatty acids by adipose tissue. Insulin lack therefore, results in general
catabolic state hyperlipidemia due to lypolysis in adipose tissue (Volk and Arquilla 1985 and
Kawachi 2004).
Diabetes mellitus is classified into type1 (insulin dependent) and type2 (insulin
independent). Type2 diabetes mellitus is ten times more common than type1 and it affects
obese subjects over 40 years (Cudworth 1978). Selective destruction of insulin secreting Bcells in pancreas occurs in type1 diabetes mellitus resulting in insulitis with evidence that
genetic factors, autoimmunity and possibly viral infection may all be etiologically involved
(Foulis 1987).
In type2 diabetes mellitus there may be both qualitative and quantitative insulin
insufficiency due to resistance to the action of insulin. These patients have to hypersecrete
insulin to achieve metabolic homeostasis with resultant B-cells exhaustion (Cerasi and Luft
1967). Diabetic macroangiopathy is most commonly affecting large muscular arteries and
microangiopathy affecting arterioles and capillaries (Williamson and Kilo 1977).
Macroangiopathy is simply atheroma, which tends to develop early and become severe in
diabetics of either sex. This, plus the fact that 50% of patients with type2 diabetes mellitus
have hypertension, results in 80% of adult diabetic deaths being due to cardiovascular,
cerebrovascular or peripheral vascular diseases together with an increased susceptibility to
bacterial infection (Volk and Arquilla 1985).
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Impaired glucose tolerance is common in elderly subjects and has been demonstrated to be
associated with increased prevalence of cardiovascular disease and its risk factors (Savage et
al 1991).
Prospective studies indicate that persons with atherosclerotic disease exhibit
abnormalities in glucose tolerance more frequently than do clinical controls (Volk and
Arquilla 1985).
The Cardiovascular Health Study data confirm prior evidence that asymptomatic
hyperglycemia is not a benign condition in the elderly and that its previously demonstrated
association with coronary disease (Mykkanen et al 1992) also extends to cerebrovascular
disease (Manolio et al 1996).
Diabetes mellitus has shown strong and consistent relationships with stroke incidence,
(Wolf et al 1977, Aronow et al 1988 and Manolio et al 1996).
Less consistent associations have been demonstrated for impaired glucose tolerance,
(Fuller et al 1983, Burchfiel et al 1994).
Diabetes mellitus induces hypercholesterolemia and a markedly increased predisposition
to atherosclerosis and when other factors are equal, the incidence of myocardial infarction is
twice as high in diabetics as in non-diabetics. There is also an increased risk of stroke and,
even more striking, perhaps a hundredfold increased risk of atherosclerosis-induced
gangrene of the lower extremities. Indeed, in the absence of diabetes mellitus,
atherosclerotic gangrene of the lower extremities is uncommon (Nerup et al 1987).
Additional studies have confirmed that asymptomatic hyperglycemia is also a significant
risk factor for coronary heart disease (Epstein 1967).
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There is evidence to suggest that some individuals respond to carbohydrate
feeding with a rise in serum lipids. Refined carbohydrates (used in cookies,
candies, pies) are especially suspect as lipogenic factors which could enhance the
serum lipid rise cholesterol deposition (Gotto et al 1980).
3. 5. Age:
Age is one of the additive risk factors of atherosclerosis (Campbell et al 1989
and Salonen and Salonen 1993). Stroke incidence rises sharply with advancing age
in middle age (Kagan et al 1980, Wolf et al 1987 and Davis et al 1987) and in the
elderly (Wolf et al 1987, Welin et al 1987, Woo and Lau 1990 and Zeiler et al
1992).
Vermeer et al in 2003 found that the incidence of silent brain infarcts on MRI in
the general elderly population strongly increases with age. Other authors found
that cerebral abnormalities, such as infarctions and white matter lesions are
frequently detected in older individuals (Awad et al 1986, George et al 1986, Meyer
et al 1992, Boone et al 1992, Bots et al 1993 and Price et al 1997).
3. 6. Gender:
Male sex was found to be an additive risk factor of atherosclerosis (McGill et al
1977, Bonithon-Kopp et al 1991 and O'Leary et al 1991) and stroke incidence was
more than three times higher in women aged 80 years and older than in women
aged 65-74 and nearly twice as high in men aged 80 years and older compared with
those aged 65-74, but stroke incidence did not differ by sex in the fullRageBrange
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borderline significant trend toward greater incidence in men aged 65-74 years than women
of the same age (Manolio et al 1996).
Gender relationships with stroke incidence show men at higher (Kannel et al 1983),
similar (Manolio and Furberg 1992) or lower (D'Alessandro et al 1992) risk than women.
The significant association of gender with stroke after excluding subclinical disease
measures suggests that any sex differences in stroke incidence in these data are related to
differences in subclinical disease between women and men (Manolio et al 1996).
1. 3. 7. Periodontitis:
Several studies have suggested that periodontitis is also associated with coronary heart
disease and cerebrovascular disease (Syrajanen et al 1989, Mattila et al 1989, DeStefano et
al 1993, Mattila et al 1993, Kweider et al 1993, Mattila et al 1995, Beck et al 1996, Joshipura
et al 1996, Grau et al 1997, Loesche et al 1998 and Morrison et al 1999).
A mechanism has been proposed whereby periodontitis creates a burden of bacterial
pathogens, antigens, endotoxins and inflammatory cytokines that contribute to the process
of atherogenesis and thromboembolic events. Certain persons may exhibit greater
expression of local and systemic mediators in response to infection and inflammation and
may thereby be at increased risk for atherosclerosis. The atherosclerosis process may result
in decreased arterial patency and/or decreased compliance of the vessel. Ultimately,
atherosclerotic lesions may fissure and/or rupture, resulting in occlusion of the vessel lumen,
precipitating a myocardial infarction or stroke (Beck et al 2001).
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Elkind et al in 1999 found that individuals with periodontal disease (abnormal probing
depth >3mm, significant attachment loss >3.5mm, or with no teeth) had greater
atherosclerotic plaque thickness.
Measures of both current and cumulative periodontitis became more severe as tooth loss
increased. A significant association was observed between tooth loss levels and carotid
artery plaque prevalence. Among those with 0-9 missing teeth, 46% had carotid artery
plaque, whereas among those with 10 missing teeth, carotid artery plaque prevalence was
60%. These data suggest that tooth loss is a marker of past periodontal disease and is
related to subclinical atherosclerosis, thereby providing a potential pathway for a
relationship with clinical events (Desvarieux et al 2003).
1.3. 8. Hypothyroidism:
Another risk factor is overt hypothyroidism which has been found to be associated with
cardiovascular disease.
Atherosclerosis occurs in the hypothyroid patient as a result of angiotensin produced
arterial constriction with its resultant damage to the intimal lining of the arteries, at which
sites cholesterol is deposited. Untreated, the cholesterol deposits increase to be eventually
replaced by calcium. When treated appropriately early enough, the cholesterol deposits can
be reabsorbed (Alford 2000 and Hak et al 2000).
1.3. 9. Aspirin intake:
The regular use of aspirin was found to reduce the risk of ischemic stroke for many
patients with clinically manifest atherosclerotic vascular
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disease (Antiplatelet Trialists Collaboration 1994). In contrast, randomized clinical trials
involving people at relatively low risk for stroke have shown an opposite trend. Although
aggregate data are inconclusive, these trials associated aspirin use with an increased risk of
stroke (Peto et al 1988, Steering Committee of the Physicians' Health Study Research Group
1989, and Early Treatment of Diabetic Retinopathy Study Investigators 1992).
In a previously reported analysis of the population-based Cardiovascular Health Study,
regular aspirin use emerged as an independent risk factor for stroke even after adjustment
for other stroke risk factors (Manolio et al 1996).
1. 3. 10. Alcohol consumption:
Alcohol consumption is a controversial risk factor, excessive alcohol intake although it is
clear that it is deleterious, moderate consumption appears to protect against stroke (Sacco et
al 1999).
It became clear that individuals who ingest 5 or more units of alcohol per day had a
significantly increased risk for ischemic stroke. Importantly, those who kept to 1 or 2 units
per day had a lower ischemic stroke risk than those who did not drink at all (Sacco 2001).
These findings support those of other studies, and the recommendation made in the
National Stroke Association Stroke Prevention Guidelines is that drinking in moderation is
beneficial for those who drink alcohol and have no health contraindications to alcohol use.
People who do not drink should not be encouraged to do so; however, those who do should
be encouraged to drink the appropriate amount (Gorelick et al 1999).
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A protective effect of low to moderate alcohol intake on cerebral infarction was not found;
moreover, increased alcohol intake was associated with brain atrophy (Ding et al 2004).
Mukamal et al in 2001 found that moderate alcohol consumption is associated with a
lower prevalence of white matter abnormalities and infarcts, thought to be of vascular
origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older
adults.
1. 3. 11. Other risk factors:
Systemic lupus erythematosus (Cederholm et al 2005), infection (Syrjänen et al 1988),
subclinical disease (Kuller et al 1995), sickle cell anemia (Rothman et al 1986), mercury and
fish oil (Virtanen et al 2005) were also found to be another risk factor for atherosclerosis.
Renal failure had been regarded as another risk factor. The blood urea level reflects the
degree of renal failure, but it is also affected by dietary protein and rate of tissue
breakdown, so the serum creatinine is a more accurate guide to renal function (McSween
and Whaley 1992) but serum creatinine level was found to be weakly related to incident
stroke as detected in models with creatinine as a linear term (Manolio et al 1996).
The incidence of stroke mortality is greater in African-American and Caribbean
Hispanic ethnic groups than in Caucasians, showing a twofold increased risk compared with
Caucasians (Sacco et al 1998. S). In these ethnic groups, risk factors may be more prevalent
and less controlled and may therefore contribute to the greater age-adjusted incidence of
stroke (Sacco et al 2001).
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Physical activity, even in the elderly, lowers the risk for stroke. In the Northern
Manhattan Stroke Study, where the average age was 69 years, physical activity did
have a protective effect against stroke. Significantly, a relatively low level of
exercise, such as walking, was sufficient to produce this effect (Sacco et al 1998. L).
This modifiable risk factor, often under-emphasized in elderly populations,
provides a relatively straightforward way to reduce stroke risk. Other "soft" risk
factors are severe obesity, hyperhomocysteinemia, xanthomatosis, hyperuricemia,
stressful lifestyle, oral contraceptives, familial background and high carbohydrate
intake.
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1.4. Aims of thesis:
1. To study the interrelationships between intima-media thickness (IMT) of
carotid artery and various risk factors which are age, gender, cigarette
smoking, diabetes mellitus, hypertension, hyperlipidemia, hypothyroidism,
number of tooth loss, periodontal index (a measure of periodontal
deterioration), serum creatinine and aspirin intake.
2. To study the interrelationships between cerebral infarction (CI) and the above
mentioned risk factors.
3. To study the interrelationships between CI and IMT of carotid artery. This
includes the measurements of the overall carotid IMT and also some of its
characteristics like the degree of stenosis, plaque surface and plaque texture.
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CHAPTER TWO
Subjects and Methods
A total number of 582 subjects (309 males and 273 females) had originally
participated in the initial steps of present research. Only 362 subjects (184 males
and 178 females) however, ran the full distance to the end line due to various
obstacles. They were referred to the Magnetic Resonance Image (MRI) Unit in the
Teaching Hospital of Najaf for various MRI examination purposes. The research
protocol consists of the followings:
-Cerebral Magnetic Resonance Image.
-Common and internal carotid Doppler ultrasonography.
-Calculation of periodontal index and number of missing teeth.
-Clinical and Laboratory investigations:
* Systolic and diastolic blood pressure.
*Fasting blood sugar.
*Lipid profile.
*Serum creatinine.
-Information about age, cigarette smoking, alcohol and aspirin.
- Physician diagnosis for hypothyroid subjects.
- Study groups.
- Data analyses.
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Patients suffering from chronic or acute infections were excluded from the study
to avoid confusion, because these infections were found to be related to increased
intima-media thickness (IMT) and cerebral infarction (CI) (Bova et al 1996 and
Grau et al 1997).
2. 1. Cerebral Magnetic Resonance Image (MRI):
The MRI protocol consisted of a sagittal T1-weighted localizing sequence. This
was followed by axial T1-weighted and axial spin-density and T2-weighted images.
All axial sequences were angled to the anterior/posterior commissure line with
5-mm scan thickness without interslice gaps and at a field of view of 24 cm
(Longstreth et al 2002).
To be considered an infarct lesion, a focal brain abnormality was required to be
a nonmass area in a vascular distribution, hyperintense on spin-density and T2weighted images. Infarcts of the cortical gray matter and deep nuclear regions and
capsule were defined as lesions bright on spin-density and T2-weighted images
(Fried et al 1991, Bryan et al 1994, Longstreth et al 1996).
Participants were regarded as having cerebral infarction according to the
previously mentioned criteria; no matter where, how many or how large the infarct
lesions were within the brain tissues. Hence, it was the same whether the subject
had small or large, single or multiple, cortical, basal or elsewhere infarcts; as far as
the criteria was the presence or absence of CI.
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2. 2. Common and internal carotid Doppler ultrasonography:
Atherosclerosis was assessed using B-mode ultrasound to measure carotid
artery IMT and some of its characteristics (Wendelhag et al 1991).
2. 2. 1. Measurements of intima-media thickness (IMT):
The measurement used in the analysis included the average IMT of the near and
far walls of left and right common carotid, and left and right internal carotid
arteries with the thickest IMT to be selected (Golden et al 2002), the actual
thickness of each lesion is measured with ultrasound instrument calipers. Plaque
was defined as any focal thickening of the intimal-medial layer of the common or
internal carotid arteries (Longstreth et al 2002).
2. 2. 2. Examination of plaque characteristics:
In addition to the measurements of IMT, the following lesion characteristics
were examined:
2. 2. 2. 1. Degree of stenosis:
Two categories of degree of stenosis were defined:
<50% was defined by duplex ultrasonography as less than 1.5m/s Doppler peak
flow velocity.
≥50% was defined by duplex ultrasonography as more than 1.5 m/s Doppler peak
flow velocity.
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Individual participants were characterized by the degree of stenosis in the most
severely affected vessel; that is, ≥50% left-sided stenosis and <50% right-sided
stenosis would place a participant in the ≥50% stenosis category (Longstreth et al
2002).
2. 2. 2. 2. Plaque surface:
Lesion surface was classified on the basis of gray-scale images as:
Smooth: This includes smooth to mildly irregular plaque surface with height
variations <0.4mm without discrete depression >2mm in width extending into the
media.
Irregular: This includes markedly irregular to ulcerated plaque surface with
height variations ≥0.4mm with or without discrete depression >2 mm in width
extending into the media.
Individual participants were characterized by the plaque surface in the most
severely affected vessel; that is, irregular left-sided plaque surface and smooth
right-sided plaque surface would place a participant in the irregular plaque
surface category (Longstreth et al 2002).
2. 2. 2. 3. Plaque texture:
Focal lesions were evaluated on the basis of gray-scale images. Lesion texture
was classified as:
Homogenous: Uniform echogenicity throughout lesion.
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Heterogeneous: Nonuniform echogenicity throughout lesion.
Individual participants were characterized by the plaque texture in the most
severely affected vessel; that is, heterogeneous left-sided plaque texture and
homogenous right-sided plaque texture would place a participant in the
heterogeneous plaque texture category (Longstreth et al 2002).
2. 3. Calculation of periodontal index and number of missing teeth:
Clinical periodontal measures collected included probing pocket depth and
gingival recession with the use of a well calibrated periodontal probe on 6 sites for
all of the remaining teeth (which were buccal, mesiobuccal, distobuccal, lingual,
mesiolingual and distolingual sites).
Periodontal index (PI) represents the average loss of gingival attachment or so
called attachment level (AL) which was calculated from the pocket depth and
gingival recession scores. Attachment level is a valid measure of historical
periodontal destruction (Beck et al 1993). The following formula was used to
calculate the PI:
PI = the sum of periodontal scores \ 6* the number of the remaining teeth
The number of missing teeth was calculated by subtraction of the number of the
remaining teeth from 32 in an assumption that every subject was having the
normal human full permanent dentition (32).
Tooth loss = 32 minus the remaining teeth.
2. 4. Clinical and Laboratory investigations:
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2. 4. 1. Systolic and diastolic blood pressure:
Hypertension was defined as physician diagnosis, use of anti-hypertensive
medications, or systolic blood pressure 140mmHg and/or diastolic blood pressure
90mmHg (Golden et al 2002).
Blood pressure was measured in the right arm after the participant had been
seated for 5min., in order to achieve the steady state, using a well calibrated
sphygmomanometer and an appropriately sized cuff (Guyton 1980).
Three measurements were taken; the mean of the second and third
measurements was used to characterize blood pressure at the visit (Golden et al
2002).
2. 4. 2. Fasting blood sugar:
Diabetes mellitus was defined as physician diagnosis, use of anti-diabetic
medications or fasting blood sugar (FBS)>140mg/dl based on 1979 American
Diabetes Association diagnostic criteria (Golden et al 2002).
2. 4. 3. Lipid profile:
Lipid profile includes laboratory investigations of low density lipoproteins, high
density lipoproteins, triglycerides and total cholesterol (LDL, HDL, TG and TC
respectively) (Friedewald 1972).
Hyperlipidemia was judged as present when laboratory investigations of serum
at presentation showed a total cholesterol level of ≥220mg/dl, a triglyceride level of
≥150mg/dl, a high density lipoproteins level of <40mg/dl, or when there was a
history of treatment (Uehara 1999).
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2. 4. 4. Serum creatinine:
Blood was collected for serum using enzymatic methods (Vangent et al 1977 and
Golden et al 2002). The normal range of serum creatinine is 0.6-1.5mg/dl (Guyton
and Hall 2000).
2. 5. Information about age, cigarette smoking, alcohol and aspirin:
2. 5. 1. Information about age:
Information about age was taken from the identification cards of subjects, but
with logical comparisons between the chronological and physiological ages due to
that considerable number of elderly Iraqis cared no identity records. Accordingly,
participants were categorized into five age groups:
Group A: 30-39 years.
Group B: 40-49 years.
Group C: 50-59 years.
Group D: 60-69 years.
Group E: > 69 years.
2. 5. 2. Information about cigarette smoking:
The smoking groups were as follows:
NS: Nonsmokers which involves subjects who never smoked at all.
XS: Exsmokers which involves subjects who had quitted smoking.
CS: Current smokers which involves subjects who were still smoking.
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Exsmokers' data were regarded as confusing border line data so
they were only discarded when to statistically deal with smoking
effects.
2. 5. 3. Information about alcohol consumption:
The reliability of data regarding alcohol intake was suspicious due
to the religious and social embarrassment. Hence, data of alcohol
effects were also not adopted.
2. 5. 4. Information about aspirin intake:
Regarding aspirin use, patients were categorized into two groups
(Kronmal et al 1998):
YES: Frequent users who were taking any dose of aspirin on at least
10 days before examination.
NO: Others.
2. 6. Hypothyroid patients:
Hypothyroid patients were asked for reports from their specialist
physicians to confirm the diagnosis of their condition.
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2. 7. Study groups:
Participants were categorized into the following study groups:
Control group: Includes subjects who were not belong to any of the other four
study groups.
Diabetes group: Includes diabetic patients.
Hypertension group: Includes hypertensive patients.
Hyperlipidemia group: Includes hyperlipidemic patients.
Hypothyroidism group: Includes hypothyroid patients.
2. 8. Data analyses: Males' and females' data were sorted separately according to
the already detailed groups. Well defined tables were constructed and various
graphs were drawn. Student's t-test was used to check the levels of significant
differences among these various groups and p<0.05 was considered statistically
significant. Simple regression analyses were done for couples of continuous
numerical data from which regression lines were drawn. Meanwhile, correlation
coefficients were calculated for these couples of variables with the statistical levels
of significance being determined for both and again, with the level of significance
being p<0.05. Presence and absence of cerebral infarction are logical values so
they were converted to numerical values in order to facilitate the statistical
analyses by regarding the presence of cerebral infarction as 1 and its absence as 0
values (Daniel 1977).
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CHAPTER THREE
Results
3. 1. Numbers of participants:
The numbers of participants in various groups & subgroups are shown in table
1. Table 1 has been constructed to inspect the numbers of subjects with cerebral
infarction to be compared with the total numbers of subjects in these groups. It is
not of use as a statistical aid, but it may clarify some of unexplained statistically
obtained results by checking the adequacy of tested observations and matching the
relative numbers of participants.
It is obvious from table 1 that there is no control non-smoker subject with
cerebral infarction in the sample of present research which does not necessarily
mean that cerebral infarction does not occur in such subjects at all, but it is rather
scarce such that it does not appear in the population of present research. The same
thing can be said for non-smoker hypothyroid and hypertensive patients.
Most of the research groups and subgroups, with few exceptions, have included
fairly enough numbers of participants, but however, further sub groupings have
reduced some numbers below the statistically informative levels as will be seen and
argued. Now, the effects of various risk factors on intima-media thickness (IMT) &
cerebral infarction (CI) will be studied separately & then the interrelationships
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between IMT & CI themselves will be highlighted.
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All = All subjects
All
M
F
NS CS YES NO CR DM HT HL HO
202/362
105 97 19 115 105 97 32 69 55 26 20
M = Males
184
13
55
56 49 15 35 30 14 11
F = Females
178
6
60
49 48 17 34 25 12
9
NS = Nonsmokers
143
72 71
12
1
CS = Current smokers
138
69 69
58 57 20 38 32 13 12
YES = Taking aspirin
163
82 81 59 65
NO = Not taking aspirin
199 102 97 84 73
CR = Control group
108
52 56 46 39
38 70
DM = Diabetic group
100
49 51 40 38
49 51
HT = Hypertensive group
86
46 40 33 33
41 45
HL = Hyperlipidemic group
32
17 15 12 13
20 12
HO = Hypothyroid group
36
20 16 12 15
15 21
7
0
9
3
6
21 31 25 18 10
8 10
41
11 38 30
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Table (1): Number of subjects in various groups and subgroups
Numbers in Bold Italic = total number of participants
Underlined numbers = number of subjects with cerebral infarction
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3. 2. Intima-media thickness & some risk factors:
3. 2. 1. In control group:
A significantly strong positive correlation is found between IMT & age (r = 0.68,
p < 0.001), but this is only in non-smokers (figure 1a). The effects of smoking may
in certain manner masked the age effects. It is clear from figure 1a that the
number of smoker control subjects without CI is statistically not small (19
subjects), but careful inspection of figure 1a shows us that there are few dispersed
data series (indicated by arrows) which may render the correlation between IMT
and age not significant in smoker control subjects. However, a trend to omit the
farthest three of these dispersed data series yielded a statistically significant
correlation (figure 1b).
The absence of similar regression lines for control non-smoker subjects with
cerebral infarction is due to the previously observed absence of such subjects
(table 1).
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Non smokers, y = 0.0109x + 0.0471, r = 0.96, P < 0.001
Smokers, y = 0.0022x + 0.5811, r= 0.19, P = NS
1.1
1
Non smokers
0.9
IMT (in mm)
0.8
Smokers
0.7
0.6
0.5
0.4
0.3
25
35
45
55
65
Age (years)
75
85
Figure (1a): Regression of IMT on age in
control smokers (n=19) & non-smokers (n=46)
without cerebral infarction. Arrows indicate the
far dispersed data series.
95
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Non smokers, y = 0.0109x + 0.0471, r = 0.96, P < 0.001
Smokers, y = 0.0111x + 0.0655, r=0.87, P <0.001
1.1
1
Smokesrs
0.9
0.8
IMT (mm)
Non- smokers
0.7
0.6
0.5
0.4
0.3
25
35
45
55
65
75
85
95
Age (years)
Figure(1b): Regression of IMT on age in control
smokers (n=16) and non- smokers (n=46) without
cerebral infarction after ommitting three of the
dispersed data series.
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The plasma lipid concentrations are also found to be strongly
correlated with IMT and with age in non-smokers (figures 2 and 3),
but not in smokers (figures 4 and 5) without cerebral infarction. The
low density lipoproteins (LDL), triglycerides (TG) and total
cholesterol (TC) are directly related while the high density
lipoproteins (HDL) are inversely related with IMT and age in nonsmokers (figures 2 and 3).
Steeper slopes, as achieved from the regression equations, are seen
in the LDL regression lines and the least slopes are seen in TG
regression lines which mean that LDL is probably the most, and TG
is probably the least, strongly related to IMT and age.
The resemblance of the regression lines of plasma lipid
concentrations on IMT to those on age consolidates the previously
concluded correlation of IMT with age (figure 1).
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LDL
y = 46.78x + 70.483, r = 0.70, P < 0.001
HDL
y = -12.578x + 56.492, r = - 0.46, P < 0.01
TG
y = 24.986x + 59.999, r = 0.47, P < 0.001
TC
y = 32.024x + 152.33, r = 0.57, P < 0.001
210
Plasma lipid concentrations (mg/dl)
190
TC
170
150
130
LDL
110
90
TG
70
50
HDL
30
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
IMT (mm)
Figure (2): Regression of plasma
lipid concentrations on IMT in
control non-smoker subjects
without cerebral infarction (n=46).
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LDL
HDL
y = 0.4089x + 77.797, r = 0.59, P < 0.001
y = -0.0954x + 53.84, r = -0.32, P < 0.01
TG
y = 0.2154x + 63.777, r = 0.36, P < 0.01
210
TC
y = 0.2953x + 155.89, r = 0.49, P < 0.001
TC
Plasma lipid concentration (mg/dl)
180
150
120
LDL
90
TG
60
HDL
30
20
30
40
50
60
70
80
90
Age (years)
Figure(3): Regression of plasma lipid
concentrations on age in control nonsmoker subjects without cerebral
infarction (n=46).
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LDL
y = 19.758x + 87.805, r = 0.4, P = NS
HDL
y = -1.8015x + 49.873, r = - 0.07, P = NS
TG
y = 1.9433x + 74.393, r = 0.03, P = NS
TC
y = 6.5861x + 167.27, r = .0.13, P = NS
210
190
Plasma lipid concentrations (mg/dl)
TC
170
150
130
110
LDL
90
TG
70
50
HDL
30
0.4
0.5
0.6
0.7
0.8
0.9
1
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1.1
IMT (mm)
Figure(4): Regression of plasma lipid
concentrations on IMT in control smoker
subjects without cerebral infarction (n=19).
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LDL
y = 0.0472x + 99.053, r = 0.08, P = NS
HDL
y = -0.0218x + 49.942, r = - 0.08, P = NS
TG
y = 0.1135x + 68.7, r = 0.19, P = NS
TC
y = 0.2107x + 158.84, r = 0.38, P = NS
210
190
TC
Plasma lipid concentrations (mg/dl)
170
150
130
110
LDL
90
TG
70
HDL
50
30
30
40
50
60
70
Age (years)
80
90
Figure(5): Regression of plasma lipid
concentrations on age in control smoker
subjects without cerebral infarction (n=19).
100
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In figures 6 and 7, the number of tooth loss and Periodontal index
(PI) are having significantly strong positive correlation with IMT
(r=0.74 and r=0.49 p<0.001 respectively).
Dwarfing the effects of PI and tooth loss on IMT, one can say that
this may be due to age effects since that PI and tooth loss are,
themselves, significantly and strongly positively correlated with age
(r=0.71 and r=0.69, p<0.001, respectively), but this notion is not
compatible with the fact that similar strong correlations have
persisted in the other four study groups and, more important, in the
five age groups down to the smaller subgroups (the figures are not
shown).
To study the effects of PI and tooth loss on IMT perfectly, a
complete separation from age effects, and possibly some other risk
factors is crucial, but this is not applicable unless a larger sample of
control population is studied.
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1.2
y = 0.0135x + 0.516, r=0.67, p<0.001
IMT (in mm)
0.8
0.4
0
0
8
16
24
Number of tooth loss
32
Figure(6): Regression of intimamedia thickness (IMT) on tooth
loss in control group (n=108).
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1.2
y=3.6698x+0.1014, r=0.49,p <0.001
1
IMT (in mm)
0.8
0.6
0.4
0.2
0
0
1
2
3
Periodontal index (in mm)
4
Figure(7): Regression of intimamedia thickness (IMT) on
periodontal index in control group
(n=108).
5
TABLE
FIG
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As seen in table 2, there are no significant differences in IMT
between control males and females and between subjects who were
taking aspirin than those who were not.
The striking result in table 2 is that there are no significant
differences in IMT between control non-smoker and smoker
subjects, and in the five age groups (table 3).
Despite the fact that there are no significant differences between
the age of non-smokers and smokers (figure 8); a trial was adopted
to match their age by excluding some subjects on either far age
extremes such that the age means became very close together, still,
nothing new after age matching (figure 9).
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Intima-media thickness (in mm)
Male
(n=52)
Female
(n=56)
p-value
Gender
Mean
SD
0.78
0.17
NS
Nonsmokers
(n=46)
Mean
SD
0.68
0.17
Smokers
(n=39)
p-value
Smoking
Mean
SD
0.66
0.17
NS
YES
(n=38)
Mean
SD
0.79
0.18
NO
(n=70)
p-value
Aspirin
Mean
SD
0.77
0.19
NS
Mean
SD
0.71
0.17
Table (2): Intima-media thickness (IMT
in mm) in control group (n=108).
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Intima-media thickness (in mm)
Nonsmokers
(n=16)
Group A (30-39 years)
Mean
SD
0.62
0.27
Nonsmokers
(n=29)
Group B (40-49 years)
Mean
SD
0.92
0.66
Nonsmokers
(n=28)
Group C (50-59 years)
Mean
SD
1.1
0.65
Nonsmokers
(n=35)
Group D (60-69 years)
Mean
SD
1.32
0.72
Nonsmokers
(n=35)
Group E (>69 years)
Mean
SD
1.76
0.91
p-value
NS
p-value
NS
p-value
NS
p-value
NS
p-value
NS
Current smokers
(n=18)
Mean
SD
1.46
1.17
Current smokers
(n=27)
Mean
SD
1.28
0.75
Current smokers
(n=31)
Mean
SD
1.54
0.66
Current smokers
(n=32)
Mean
SD
1.84
1.07
Current smokers
(n=30)
Mean
SD
1.63
1.23
Table (3): Relationships between intimamedia thickness (IMT) and smoking in the
five age groups.
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1
NS
IMT (in mm)
0.8
0.6
0.4
Non-smokers (n=46) Smokers (n=39)
Figure(8): Intima-media thickness
(IMT) in control non-smoker &
current smoker groups.
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1
NS
IMT (in mm)
0.9
0.8
0.7
Non-smokers (n=31) Smokers (n=39)
Figure(9): Intima-media thickness
(IMT) in control non-smoker & current
smoker groups. The insert reveals age
matching.
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Figure 10 shows us that, after age matching, there are no significant
differences in IMT between control subjects who were taking aspirin
than those who were not.
After age matching, there are also no significant differences in
IMT between control males (0.69mm ± 0.16mm) and females
(0.65mm ± 0.17mm).
These results reoccurred in the other four study groups and in the
five age groups (figures not shown) confirming that the already
mentioned outcomes are the final decision from the present data.
Regarding the IMT and serum creatinine concentrations, there
was no any significant relation to be recorded.
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1.2
1
IMT (in mm)
NS
0.8
0.6
0.4
YES (n=38)
NO (n=64)
Figure(10): Intima-media thichness
(IMT) in YES & NO aspirin groups.
The insert reveals age matching.
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3. 2.1. In the other study groups:
IMT is significantly lower in non-smoker control group (0.66mm ± 0.17mm)
than in non-smoker hypertensive group (1.35mm ± 0.74mm) (p<0.001), but not in
the other study groups (diabetic; 1.31mm ± 0.73mm, hyperlipidemic; 2.12mm ±
0.8mm & hypothyroid, 1.63mm ± 1.04mm) (p=NS). Again, these results are before
age matching, but they are not the same thereafter (figures 11-14). Here, IMT is
significantly lower in non-smoker control group than in non-smoker diabetic,
hypertensive and hypothyroid groups (figures 11, 12 and 14 respectively), but not
in hyperlipidemic group (figure 13).
As shown in figure 13, only twelve hyperlipidemic patients may not be sufficient
to conclude a scientific interpretation from the results especially with such
multifactorial condition.
Smoking effects are also studied in every study group separately as seen in table
4 which shows no significant differences between smokers and non-smokers in all
of the five study groups. Age matching for every study group separately had
severely reduced the remaining numbers of observations such that they affected
the statistical decision. Hence, age matching is not done in the very small
subgroups.
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2.5
p<0.02
IMT (in mm)
2
1.5
1
0.5
Control (n=46) Diabetic (n=48)
Figure(11): Intima-media thickness
(IMT) in non-smoker control & diabetic
groups. The insert reveals age
matching.
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2.5
p<0.001
IMT (in mm)
2
1.5
1
0.5
0
Control (n=46) Hypertensive (n=29)
Figure(12): Intima-media thickness
(IMT) in non-smoker control &
hypertensive groups. The insert
reveals age matching.
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3
NS
2.5
IMT (in mm)
2
1.5
1
0.5
0
Control (n=28) Hyperlipidemic (n=12)
Figure(13): Intima-media thickness
(IMT) in non-smoker control &
hyperlipidemic groups. The insert
reveals age matching.
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3
p<0.001
2.5
IMT (in mm)
2
1.5
1
0.5
0
Control (n=32) Hypothyroid (n=12)
Figure(14): Intima-media thickness
(IMT) in non-smoker control &
hypothyroid groups. The insert
reveals age matching.
TABLE
FIG
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Intima-media thickness (in mm)
Nonsmokers
(n=46)
Control group
Mean
SD
0.66
0.17
Nonsmokers
(n=40)
Diabetic group
Mean
SD
1.31
0.73
Nonsmokers
(n=33)
Hypertensive group
Mean
SD
1.35
0.74
Nonsmokers
(n=12)
Hyperlipidemic group
Mean
SD
2.12
0.80
Nonsmokers
(n=12)
Hypothyroid group
Mean
SD
1.63
1.07
p-value
NS
p-value
NS
p-value
NS
p-value
NS
p-value
NS
Current smokers
(n=39)
Mean
SD
0.79
0.18
Current smokers
(n=38)
Mean
SD
1.79
1.05
Current smokers
(n=33)
Mean
SD
1.77
0.84
Current smokers
(n=13)
Mean
SD
2.60
1.25
Current smokers
(n=15)
Mean
SD
1.66
0.93
Table (4): Intima-media thickness (IMT) in
non-smokers and current smokers in the
five study groups.
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3. 2. Cerebral infarction and some risk factors:
Cerebral infarction (CI) is, statistically, a logical (not numerical) value i.e. it is either
present (takes number 1) or absent (takes number 0).
Accordingly, the means and standard deviations were calculated and multiplied by 100%
to obtain the percentage of occurrence of cerebral infarction (CI%) for statistical purposes
(Daniel 1977).
3. 2. 1. In control group:
There is significantly higher CI% in subjects who were taking aspirin than those who
were not (p<0.001) (table 5 and figure 15).
From now on, in order to study the effects of risk factors other than aspirin intake,
subjects on aspirin must be excluded to avoid confusion due to the overlapping effects of
aspirin intake. Doing so, no significant differences in CI% are found between males and
females and between smokers and non-smokers (figures 16 and 17 respectively). Age
matching had severely reduced the remaining numbers of observations such that they
affected the statistical decision. Hence, age matching is not done after excluding subjects
who were taking aspirin. However, age matching is done without excluding subjects who
were taking aspirin and smokers are found to have significantly higher CI% than nonsmokers (figure 18).
Table 6 shows us that CI% is significantly higher in smokers than in non-smokers in all
of the five age groups with the exception of age group E (>69 years). In that age group, the
cumulative risk factors have made the patients' condition so bad to differentiate between
B
smokers and non-smokers.
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Percentage of cerebral infarction (CI %)
Male
(n=52)
Female
(n=56)
p-value
Gender
Mean
SD
28.84
45.74
NS
Nonsmokers
(n=46)
Mean
SD
30.35
46.39
Smokers
(n=39)
p-value
Smoking
Mean
SD
0
0
NS
YES
(n=38)
Mean
SD
51.28
50.63
NO
(n=70)
p-value
Aspirin
Mean
SD
55.26
50.38
p<0.001
Mean
SD
15.71
36.65
Table (5): Percentage of cerebral infarction
(CI%) in control group (n=108).
FIG
TABLE
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110
Percentage of
cerebral infarction (CI%)
90
70
p<0.001
50
30
10
YES (n=38)
NO (n=64)
Figure(15): Percentage of cerebral
infarction (CI%) in YES & NO aspirin
groups. The insert reveals age
matching.
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70
NS
60
Percentage of cerebral infarction (CI%)
50
40
30
20
10
0
Males (n=34)
Females (n=36)
Figure(16): Percentage of cerebral
infarction (CI%) in control males &
females taking no aspirin.
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80
NS
Percentage of cerebral infarction (CI%)
60
40
20
0
Nonsmokers (n=36)
Smokers (n=20)
Figure(17): Percentage of
cerebral infarction (CI%) in
control non-smoker & current
smoker groups taking no aspirin.
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p<0.001
Percentage of cerebral
infarction (CI%)
100
75
50
25
0
Non-smokers (n=31) Smokers (n=39)
Figure(18): Percentage of cerebral
infarction (CI%) in control non-smoker
& current smoker groups. The insert
reveals age matching.
TABLE
FIG
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Percentage of cerebral infarction
(CI%)
Nonsmokers
(n=16)
Group A (30-39 years)
Mean
SD
0
0
Nonsmokers
(n=29)
Group B (40-49 years)
Mean
SD
10.34
30.99
Nonsmokers
(n=28)
Group C (50-59 years)
Mean
SD
0
0
Nonsmokers
(n=35)
Group D (60-69 years)
Mean
SD
17.14
38.23
Nonsmokers
(n=35)
Group E (>69 years)
Mean
SD
28.57
45.83
p-value
p<0.001
p-value
p<0.001
p-value
p<0.05
p-value
p<0.001
p-value
NS
Current smokers
(n=18)
Mean
SD
83.33
38.34
Current smokers
(n=27)
Mean
SD
88.88
32.02
Current smokers
(n=31)
Mean
SD
87.09
34.7
Current smokers
(n=32)
Mean
SD
78.12
42
Current smokers
(n=30)
Mean
SD
80
40.68
Table (6): Percentage of cerebral infarction
(CI %) in non-smokers and current.
smokers in the five age groups
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Tooth loss and PI are having no significant relation to CI% (figures
19 and 20 respectively). This is a genuine relation between PI, tooth
loss and CI% due to that PI and tooth loss, themselves, are
significantly and strongly positively correlated with age as stated
before (r=0.71 and r=0.69, p<0.001, respectively), i.e. when age
matching is done for subjects with and without cerebral infarction;
PI and tooth loss would be simultaneously matched being nearly
exactly the same in subjects with and without CI, a matter that may
interfere with the randomness of selection.
No significant effect is detected for serum creatinine
concentration on CI% even after excluding aspirin users and doing
age matching.
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NS
32
Number of Tooth loss
24
16
8
0
Without CI (n=76)
With CI (n=32)
Figure(19): Number of tooth loss
in control groups with & without
cerebral infarction (CI).
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NS
Periodontal index (in mm)
3.8
3.1
2.4
1.7
1
Without (n=76)
With (n=32)
Figure(20): Periodontal index
in control groups with &
without cerebral infarction.
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3. 2. 2. In the other study groups:3. 2. 2. In the other study groups:
The age of subjects with cerebral infarction (68.33years ± 13.23years) was significantly
higher than that of subjects without cerebral infarction (49.11years ± 11.01years) (p<0.001).
There are significantly higher CI% in non-smoker diabetic (figure 21), hypertensive
(figure 22), hyperlipidemic (figure 23) and hypothyroid (figure 24) groups than in nonsmoker control group after age matching (p<0.001). There are also significantly higher CI%
in diabetic (figure 25), hypertensive (figure 26), hyperlipidemic (figure 27) and hypothyroid
(figure 28) groups than in control group in subjects taking no aspirin (p<0.001, p<0.05,
p<0.02 and p<0.05 respectively).
Table 7 shows us significantly higher CI% in smokers than in non-smokers in diabetic
group (p<0.001), hypertensive group (p<0.05) and hypothyroid group (p<0.001), but no
significant differences in the other two (control and hyperlipidemic) groups.
The age of subjects with cerebral infarction (68.33years ± 13.23years) was significantly
higher than that of subjects without cerebral infarction (49.11years ± 11.01years) (p<0.001).
There are significantly higher CI% in non-smoker diabetic (figure 21), hypertensive
(figure 22), hyperlipidemic (figure 23) and hypothyroid (figure 24) groups than in nonsmoker control group after age matching (p<0.001). There are also significantly higher CI%
in diabetic (figure 25), hypertensive (figure 26), hyperlipidemic (figure 27) and hypothyroid
(figure 28) groups than in control group in subjects taking no aspirin (p<0.001, p<0.05,
p<0.02 and p<0.05 respectively).
Table 7 shows us significantly higher CI% in smokers than in non-smokers in diabetic B
group (p<0.001), hypertensive group (p<0.05) and hypothyroid group (p<0.001), but no
significant differences in the other two (control and hyperlipidemic) groups.
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75
Percentage of cerebral infarction (CI%)
p<0.001
50
25
0
Control (n=46) Diabetic (n=48)
Figure(21): Percentage of cerebral
infarction (CI%) in non-smoker control
& diabetic groups. The insert reveals
age matching.
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p<0.001
Percentage of cerebral infarction (CI%)
40
30
20
10
0
Control (n=46) Hypertensive (n=29)
Figure(22): Percentage of cerebral
infarction (CI%) in non-smoker
control & hypertensive groups. The
insert reveals age matching.
B
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p<0.001
Percentage of cerebral infarction (CI%)
105
90
75
60
45
30
15
0
Control (n=28) Hyperlipidemic (n=12)
Figure(23): Percentage of cerebral
infarction (CI%) in non-smoker control
& hyperlipidemic groups. The insert
reveals age matching.
B
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Percentage of cerebral infarction (CI%)
40
p<0.001
30
20
10
0
Control (n=32) Hypothyroid (n=12)
Figure(24): Percentage of cerebral
infarction (CI%) in non-smoker control
& hypothyroid groups. The insert
reveals age matching.
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140
p<0.001
Percentage of cerebral infarction (CI%)
120
100
80
60
40
20
0
Control (n=70)
Diabetic (n=51)
Figure(25): Percentage of
cerebral infarction (CI%) in
control & diabetic groups taking
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140
120
p<0.05
Percentage of cerebral infarction (CI%)
100
80
60
40
20
0
Control (n=70)
Hypertensive (n=45)
Figure(26): Percentage of
cerebral infarction (CI%) in
control & hypertensive groups
taking no aspirin
B
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p<0.02
Percentage of cerebral infarction (CI%)
120
80
40
0
Control (n=70)
Hyperlipidemic (n=12)
Figure(27): Percentage of
cerebral infarction (CI%) in
control & hyperlipidemic groups
taking no aspirin
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120
Percentage of cerebral infarction (CI%)
100
p<0.05
80
60
40
20
0
Control (n=70) Hypothyroid (n=21)
Figure(28): Percentage of
cerebral infarction (CI%) in
control & hypothyroid groups
taking no aspirin.
TABLE
FIG
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Percentage of cerebral infarction
(CI %)
Nonsmokers
(n=46)
Control group
Mean
SD
51.28
50.63
Nonsmokers
(n=40)
Diabetic group
Mean
SD
100
0
Nonsmokers
(n=33)
Hypertensive group
Mean
SD
96.96
17.4
Nonsmokers
(n=12)
Hyperlipidemic
group
Mean
SD
100
0
Nonsmokers
(n=12)
Hypothyroid group
Mean
SD
80
41.4
p-value
NS
p-value
p<0.001
p-value
p<0.05
p-value
NS
p-value
p<0.001
Current smokers
(n=39)
Mean
SD
0
0
Current smokers
(n=38)
Mean
SD
22.5
42.29
Current smokers
(n=33)
Mean
SD
9.09
29.19
Current smokers
(n=13)
Mean
SD
50
52.22
Current smokers
(n=15)
Mean
SD
8.33
28.86
Table (7): Relationships between
Percentage of cerebral infarction (CI %)
and smoking in the five study groups.
FIG
TABLE
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3. 3. Intima-media thickness and cerebral infarction:
In control group; no significant differences are observed in IMT
between subjects with and without CI after age matching (figure 29).
It is apparent that the age effects have overlapped the overall
IMT effects on CI, but should that be the case with some of IMT
characteristics is to be immediately explored. The emphasized
characteristics of IMT are the degree of stenosis, plaque surface and
plaque texture which are studied in relation to CI% in the whole
population because some characteristics are absent or scarce in
control group (table 8). After age matching, subjects with ≥50%
degree of stenosis have been shown to have significantly higher CI%
than subjects with <50% degree of stenosis (figure 30), and subjects
with markedly irregular to ulcerated plaque surface have been
shown to have significantly higher CI% than subjects with smooth to
mildly irregular plaque surfaces ( figure 31) while there is no
significant difference in CI% between subjects with heterogeneous
plaque texture and those with homogenous plaque texture (figure B
32).
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1.2
1.1
NS
IMT (in mm)
1
0.9
0.8
0.7
0.6
Without CI (n=54)
With CI (n=32)
Figure(29): Intima-media thickness
(IMT) in control groups with &
without cerebral infarction (CI). The
insert reveals age matching.
TABLE
FIG
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Degrees of stenosis
Stenosis < 50% ( n=323 )
Plaque surface
Smooth ( n=216 )
Plaque texture
Percentage of cerebral infarction (CI%)
Homogenous ( n=228 )
Stenosis > 50% ( n=29 )
p-value
Mean
SD
50.77
50.07
NS
Mean
SD
97.43
16.01
Irregular ( n=67 )
p-value
Mean
SD
54.62
49.9
p<0.001
Mean
SD
97.01
17.14
Heterogeneous ( n=55 )
p-value
Mean
SD
56.14
49.73
p<0.001
Mean
SD
100
0
Table (8): Percentage of cerebral infarction
(CI%) with various plaque characteristics
before age matching.
B
FIG
E
H
Percentage of cerebral infarction (CI%)
125
p<0.001
100
75
50
25
0
LOW (n=161)
UP (n=39)
Figure(30): Percentage of cerebral
infarction (CI%) in LOW (<50%) and
UP(>=50%) groups of degree of stenosis.
The insert reveals age matching.
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Percentage of cerebral infarction (CI%)
120
p<0.001
80
40
0
Smooth (n=138) Irregular (n=67)
Figure(31): Percentage of cerebral
infarction (CI%) in smooth & irregular
plaque surface groups. The insert
reveals age matching.
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4
NS
IMT (in mm)
3
2
1
0
Smooth (n=138) Irregular (n=67)
Figure(33): Intima-media thickness
(IMT) in smooth & irregular plaque
surfacegroups. The insert reveals
age matching.
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Considerable attention must be paid to the fact that after age
matching, IMT is not significantly higher in subjects with irregular
plaque surface than in subjects with smooth plaque surface (figure
33), and it is not significantly higher in subjects with heterogeneous
plaque texture than in subjects with homogenous plaque texture
(figure 34). This means that CI% is more likely to be related to the
plaque characteristics than to the overall increase in IMT.
B
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Percentage of cerebral
infarction (CI%)
105
NS
70
35
0
Homo (n=136) Hetero (n=55)
Figure(32): Percentage of cerebral
infarction (CI%) in homogenous (Homo) &
heterogeneous (Hetero) plaque texture
groups. The insert reveals age matching.
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5
4
NS
IMT (in mm)
3
2
1
0
Homo (n=136)
Hetero (n=55)
Figure(34): Intima-media thickness (IMT)
in homogenous (Homo) & heterogeneous
(Hetero) plaque texture groups. The insert
reveals age matching.
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CHAPTER FOUR
Discussion
4. 1. Relationships between atherosclerosis and cerebral infarction with some of their risk
factors:
4. 1. 1. Gender:
Atherosclerotic coronary heart disease is predominantly a disease of men especially at
younger ages with the prevalence in the fourth decade is three times that in women (Dawber
1980). This difference decreases with age but remains higher at all ages in men. Possible
explanations include levels of estrogenic hormones (McGill and Stern 1977) and higher
levels of high density lipoproteins (HDL) which is known to be antiatherogenic in
premenopausal women (Gotto 1979). A significant correlation between CI and female sex
was found in previous studies (Uehara et al 1999 and Shimada et al 1990). However, male
sex has been noted as a risk factor for CI in some other studies (Ricci et al 1993, Jørgensen
et al 1994 and Davis et al 1996), while in present research, CI% and measurements of IMT
were not significantly different in either sex (tables 2 and 5).
Manolio et al stated that stroke incidence did not differ by sex in the full age range,
although there was greater incidence in men aged 65 to 74 years than women of the same
age (Manolio et al 1996). While some other published data showed that men at higher
(Kannel et al 1983), similar (Bamford et al 1988), or lower (D'Alessandro et al 1992) risk
than women. High levels of HDL were found in women before the postmenopausal age
(Women's Health Study Research Group 1992) which may be the protective factor from
atherosclerosis in women at that period of life.
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Although the association with female sex was restricted to CI in the white matter, the
reason for the discrepancy among studies is not clear. Gender was not significantly
associated with stroke in multivariate analysis, and no significant interactions with gender
were detected in these models. The significant association of gender with stroke after
excluding subclinical disease measures suggests that any sex differences in stroke incidence
in these data are related to differences in subclinical disease between women and men
(Manolio et al 1996).
4. 1. 2. Age:
The age of subjects with CI is significantly higher than the age of those without CI in present
research population, and strong positive relation is found between age and IMT in non-smokers
(figures 1a and 1b) and in current smokers (figure 1b), in addition to that age matching has changed
many interrelationships between IMT and CI in one hand, and their risk factors in the other hand
(figures 9, 10,…onwards). All these facts may suggest strong age effects on IMT and CI in present
research population. Some very few dispersed data of smokers on either extremes of the scatter
diagram in figure 1a has affected the normal positive regression of IMT on age. These biased data may
not only be related to age factor or smoking habit alone. Instead, other factors, not to speak about race
or ethnicity, but gender, physical activity, alcohol consumption, serum creatinine, aspirin intake,
periodontal status, various infections and a long list of interlacing risk factors that are, though
separately weak, but may be additively strong.
In previous studies, the presence of CI had been linked to age (Brant-Zawadzki et al 1985,
Koboyashi et al 1991, Bryan et al 1997 and Price et al 1997). The majority of previous studies
demonstrated that age strongly and independently correlated with CI anywhere in brain tissues
(Shimada et al 1990, Nishino et al 1993, Boon et al 1994, Jørgensen et al 1994, Davis et al 1996 and
Kobayashi et al 1997), other study had demonstrated that age was a common risk factor for
R
B
E
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CI in both the white matter and basal ganglia (Uehara et al 1999), these results, together
with the fact that most of cases with CI in the basal ganglia also had CI in the white matter,
suggest that CI initially appears in the white matter in association with aging and
subsequently appears in the basal ganglia in association with development of atherosclerosis
(Furuta et al 1991). Stroke incidence is known to be strongly related to age (Kagan et al
1980 and Kannel et al 1983). Longstreth et al in 2002 stated that stroke incidence was more
than three times higher in women aged 80 years and older than in women aged 65 to 74, and
nearly twice as high in men aged 80 years and older compared with those aged 65 to 74.
Hence, the fact that the age relationship remained after adjustment for other risk factors
that increase with age (such as blood pressure, diabetes, and subclinical disease) suggests
that age itself is somehow a risk factor for stroke.
4. 1. 3. Smoking:
Figures 1a and 1b revealed that only three far dispersed data series in control smoker
subjects have rendered the age-related progression of IMT not significant in smokers. This
masking effect of smoking over a strong IMT risk factor like age, together with the
significantly higher CI% in smokers than in non-smokers (figure 18) may suggest strong
association, when other risk factors are adjusted, between smoking in one hand and IMT
and CI% in the other hand which confirm the previously well documented deleterious
smoking effects (Kannel et al 1976, Kannel and Thom 1984, Stamler et al 1993 and
Zanchetti 1997).
Table 2 and figure 9 reveal no significant differences in IMT between non-smokers and smokers in
control group. The previously blamed long list of other interlacing risk factors (gender, physical
activity, alcohol consumption, serum creatinine, aspirin intake, periodontal status,…) are, together with
those not yet discovered factors and the small study sample may be alleged to play a role.
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Another possible explanation is that the result in figure 1 is for those subjects without
cerebral infarction while that in table 2 is for the whole control group (with and without
cerebral infarction) because there is no control non-smoker subject with cerebral infarction
in present sample to be compared with the other study groups (call on table 1) i.e. the
masking smoking effects may be in certain way more obvious in control subjects without CI
than those with CI.
Table 3 reveals no significant differences in IMT between non-smokers and smokers in
the five age groups. This seems to be easily interpreted since that each age group contains all
of the other possible risk factors (before all, come up the hyperlipidemic, hypertensive,
diabetic and hypothyroid groups) because we could not do further subgrouping for the five
age groups and the two smoking groups into further five study groups since that such
subgrouping has abolished or extremely reduced the numbers of subjects in these subgroups
to statistically useless numbers.
Table 4 also shows us no significant differences in IMT between non-smokers and smokers in the
five study groups (namely control, diabetic, hypertensive, hyperlipidemic, and hypothyroid groups)
possibly due to the superimposition of age effects, again, because further subgrouping for these five
study groups and two smoking groups into further five age groups has also abolished or extremely
reduced the numbers of subjects in these subgroups to statistically useless numbers. Another possible
explanation is that the results in table 4 are for the whole population (with and without cerebral
infarction) while in figure 1 it was for those subjects without cerebral infarction because there is no
control non-smoker subject with cerebral infarction in present sample to be compared with the other
study groups (call on table 1).
The strong superimposing smoking effects are also noticeable when the significant correlations
between IMT and plasma lipid concentrations in figures 2 and 3 are nullified in figures 4 and 5
respectively.
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Although table 5 reveals no significant differences in CI% between non-smokers and
smokers, but this is found to be due to the overlapping age effects as seen in figure 18 where
significantly higher CI% in smokers than in non-smokers are observed after age matching.
Some authors reported that smoking habit is associated with CI in large population-based
studies (Howard et al 1994, Howard et al 1998 and Longstreth et al 1998). This finding was
not replicated in other study (Golden et al 2002). This lack of association in the latter study
had been attributed to the relatively small sample size in that study.
It was found that endothelial dysfunction, altered lipid metabolism, and adrenergic
stimulation induced by smoking can lead to vascular damage, augmenting atherosclerotic
changes of hypertension and dyslipidemia (Hays et al 1996, Villablanca et al 2000, and
Golden et al 2002).
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4. 1. 4. Diabetes mellitus:
Figure 11 reveals significantly higher IMT in diabetic than in control groups. The
mechanism for the deleterious effect of hyperglycemia on the development of atherosclerosis
may well be the advanced glycation endproducts (AGE) since it was shown that serum total
AGE in type2 diabetes is higher in those with clinical coronary heart disease than in those
without coronary heart disease (Kilhovd et al 1999). The vascular complications of diabetes
mellitus have been proved to be associated with atherosclerosis (Naka 2004).
Diabetes mellitus causes hyperlipidemia, namely hypercholesterol- emia and leads to
premature and severe atherosclerosis which tends to develop early and become severe in
diabetics of either sex. This, plus the fact that 50% of patients with type2 diabetes mellitus
have hypertension, results in cardiovascular, cerebrovascular or peripheral vascular
diseases (Volk and Arquilla 1985). Volk and Arquilla also claimed that atherosclerotic disease
exhibit abnormalities in glucose tolerance more frequently than do clinical controls. Impaired glucose
tolerance is common in elderly subjects and has been demonstrated to be associated with
increased prevalence of cardiovascular disease and its risk factors (Savage et al 1991).
Insulin is a major anabolic hormone. In addition to its other functions, it promotes the
uptake of free fatty acids by adipose tissue and insulin lack therefore, results in general
catabolic state with increased plasma lipid concentrations (McSween and Whaley 1992 and
Kawachi 2004).
Figures 21 and 25 show us significantly higher CI% in diabetic than in control groups
after adjustments for age and aspirin risk factors respectively. These results confirm prior
evidence that asymptomatic hyperglycemia is not a benign condition and that its previously
demonstrated association with coronary disease also extends to cerebrovascular disease
(Mykkanen et al 1992). Wolf et al in 1977 and Aronow et al in 1988 stated that diabetes has
shown strong and consistent relationships with stroke incidence. Less consistent associations
have been demonstrated for impaired glucose tolerance (Fuller et al 1983 and Burchfiel et al
1994).
4. 1. 5. Hypertension:
Figure 12 reveals significantly higher IMT in control than in hypertensive groups. The
association between hypertension and atherosclerosis had been thoroughly documented
(Kissane 1990 and Liu 2003) and it had been found that hypertension is a major risk factor
for atherosclerosis at all ages and, after age 45, may well be more important than
hypercholesterolemia (Kannel et al 1970.E). Both systolic and diastolic blood pressure has
been consistently shown to be associated with increased risk of ischemic heart diseases (Bots
et al 1993.I) but there is a considerable clinical debate as to the levels above which the risk is
increased (Braunwald 1991).
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Figures 22 and 26 reveal significantly higher CI% in hypertensive than in control groups
after adjustments for age and aspirin risk factors respectively. The presence of CI in the
brain had been linked to hypertension (Shimada et al 1990, Koudstaal et al 1991 and Ikeda
et al 1994), but hypertension was a significant factor for CI in the white matter not in the
basal ganglia (Uehara et al 1999). They suggested that CI initially appear in the white
matter in association with aging and hypertension and subsequently appear in the basal
ganglia in association with development of atherosclerosis because hypertension accelerates
the pathological process in the medullary arteries supplying the white matter (Furuta et al
1991). It had long been known to be a major risk factor for stroke (Kannel et al 1970.M),
with systolic pressure appearing to be a stronger risk factor than diastolic (Rutan et al
1988). Although antihypertensive treatment markedly reduces the increased risk of stroke
associated with hypertension (SHEP Cooperative Research Group 1991), it may not be
reasonable to assume that it eliminates this risk entirely, especially when treatment may
have begun shortly before an event (Amery et al 1991).
4. 1. 6. Hyperlipidemia:
Highly significant correlations are observed between IMT and plasma lipid concentrations in
control non-smoker (figure 2) and smoker (figure 4) subjects without cerebral infarction where the
LDL, TG and TC are shown to correlate positively, and the HDL negatively, with IMT. These findings
seem not to be due to aging process since the plasma lipid concentrations are having no significant
correlations with age in the already analyzed groups (figures 3 and 5). It is also observed in figure 13
that there is a significantly higher IMT in hyperlipidemic than in control groups. The independent
effects of lipids and lipoproteins on atherosclerosis were thoroughly documented (Stiko et al 1996, Zhu
et al 1998, Davignon et al 2005), with the LDL (Liu et al 2005 and Zhau etal 2005), TG (Oliva et al 2005)
and TC (Giannattasio et al 2005) being directly related to IMT, while HDL (Navab et al 2001, Brundert
2005 and Ma 2005) was inversely related to IMT.
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Figures 23 and 27 reveal significantly higher CI% in hyperlipidemic than in control groups
after adjustments for age and aspirin risk factors respectively. HDL was found to be
protective against stroke, whereas LDL increased the risk (Kargman et al 1999 Navab et al
2001). Sacco in 2001 stated that if stroke is subdivided into atherosclerotic (large artery
carotid disease, intracranial atherosclerotic disease) and non-atherosclerotic (cryptogenic,
lacunar and cardio-embolic strokes) categories; the protective effect of HDL is increased
still further in events of atherosclerotic origin. Greater protection with intermediate and
high HDL levels was seen in the atherosclerotic compared with the non-atherosclerotic
subgroup. This suggests that the effect of HDL may be greater in the atherosclerotic stroke
subgroup (Sacco 2001).
4. 1. 7. Hypothyroidism:
Figure 14 reveals significantly higher IMT in hypothyroid than in control non-smoker
groups after adjustments for age. And figures 24 and 28 reveal significantly higher CI% in
hypothyroid than in control non-smoker groups after adjustments for age and aspirin risk
factors respectively. Hypothyroidism was found to be a strong indicator of risk for
atherosclerosis and myocardial infarction in elderly (Hak et al 2000). Atherosclerosis occurs
in the hypothyroid patient as a result of angiotensin produced arterial constriction with its
resultant damage to the intimal lining of the arteries, at which sites cholesterol is deposited
(Richard 2000), and with the role of angiotensin II in medial hypertrophy and macrophage
infiltration (Liu et al 2003).
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4. 1. 8. Serum Creatinine:
Creatinine had been associated in a cross-sectional study with prevalent MRI-defined CI
(Longstreth et al 1998) and in longitudinal studies with incident stroke (Manolio 1996,
Wannamethee et al 1997). The risk was higher for those with creatinine of 1.3 mg/dl. The
association with creatinine may simply reflect the deleterious effects of hypertension on a
vascular bed (Kurokawa 1996) other than the brain, although direct effects of renal
insufficiency on small vessels have also been proposed (Lammie et al 1997). In addition,
renal insufficiency is associated with elevated plasma homocysteine levels (Wollesen et al
1999) which in turn have been associated with covert infarcts and white matter changes
(Matsui et al 2001, van Dijk et al 2001 and Longstreth et al 2002). Renal insufficiency may
be also due to chronic or acute infection which was found to be related to increased IMT
and CI (Grau et al 1997). In present research, no significant relation between creatinine,
IMT and CI is observed which does not necessarily mean that there is no association, but
the expected association may be superimposed by stronger risk factors like age, smoking,
plasma lipid concentrations, hypertension, diabetes mellitus and aspirin intake.
4. 1. 9. Aspirin:
Figure 10 reveals no significant relation between IMT and aspirin intake in control nonsmoker subjects after age matching. Aspirin had been variably reported to increase systolic
blood pressure and to antagonize the effect of certain antihypertensive drugs and
hypertension is a strong, prevalent risk factor for atherosclerosis (Manolio et al 1996), but
the direct proposed role of aspirin in atherosclerosis is still ambiguous.
Table 5 and Figure 15 reveal significantly higher CI% in subjects who were taking aspirin than in
subjects who were not, before and after adjustments for age respectively. Thrombo- genic effects of
aspirin have been demonstrated experimentally, particularly at high doses, and possibly relate to
inhibition of endothelially derived prostacyclin synthesis or, in some patients, increase in platelet
adhesiveness (Kelton et al 1978, Zimmermann et al 1980, Buchanan et al 1981 and Buchanan and
Brister 1995). Hypothetically, a separate and competing effect of aspirin to enhance thrombosis would
be detectable in low-risk patients, in contrast to those with manifest vascular disease, in
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which the antiplatelet effect dominates. Aspirin in doses that reduce systemic prostacyclin
appear to inhibit intrinsic thrombolytic mechanisms (Levin et al 1989 and Bednar et al
1996) possibly by interference with nitric oxide synthase (Amin et al 1995, Aeberhard et al
1995 and Bednar et al 1997).
Aspirin had been associated with increased risk of stroke in healthy male physicians
(Steering Committee of the Physicians' Health Study Research Group. In Strong et al 1989),
elderly persons with atrial fibrillation (Stroke Prevention in Atrial Fibrillation Study Group
Investigators 1990), and unselected elderly persons (Paganini-Hill et al 1989), but, yet the
mechanism for this association is not clear. Given the antiplatelet properties of aspirin, an
increased risk of hemorrhagic stroke might be understandable in aspirin users, but both
non-hemorrhagic and hemorrhagic stroke risk were increased in these studies. This
relationship will remain difficult to understand (Manolio et al 1996).
4. 1. 10. Periodontitis and tooth loss:
Figures 6 and 7 reveal significantly positive correlations between IMT in one hand and
tooth loss and periodontal index (PI) respectively in the other hand in control group. Age
matching was not employed because of the significantly positive correlations between age in one hand
and tooth loss and PI respectively in the other hand in control group (r=0.53 and r=0.41 respectively,
p<0.001) which means that to match age; tooth loss and PI will be simultaneously matched and the
randomness of sample may then be questioned. Tooth loss had been linked to ischemic heart disease
(Paunio et al1993). Periodontitis represents a burden of bacteria, endotoxin, and proinflammatory
cytokines that may be alleged to contribute to atherogenesis and thromboembolic events (Williams
1990, Beck et al 1996 and Stoll et al 2004), cerebrovascular disease (Wu et al 2000) and to decrease the
antiatherogenic potency of high density lipoprotein (Pussinen et al 2004). Monocytes, lymphocytes and
macrophages which were found to play an important pathogenetic role in periodontitis; may play the
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same role in atherosclerosis (Ross 1993, Beck et al 1996, Aslanian et al 2004, Liu et al 2005
and Murata et al 2005). Streptococcus sanguis, a microbe of the normal oral flora, can
induce platelet aggregation and may thus be thrombogenic when allowed to enter the
systemic circulation as in periodontitis (Herzberg and Meyer 1996). Furthermore, acute and
possibly exacerbating chronic infection can modify established vascular risk factors by
reducing glucose tolerance (Sammalkorpi et al 1988) and moving serum lipids toward a
profile that is more atherogenic (Sammalkorpi 1989). Beck and coworkers in 1996
hypothesized that subjects with a genetically determined strong monocytic response to
bacterial antigens could be at high risk for developing both periodontal disease and
atherosclerosis. A systemic challenge with bacteria or endotoxin can induce inflammatory cell
infiltration into large arteries, vascular smooth muscle proliferation, and other sequelae, which are also
prominent features in the natural history of atherogenesis (Lopes-Virella et al 1985 and Marcus and
Hajjar 1993). There could also be common genetic factors associated with both periodontal disease and
cardiovascular disease (Offenbacher et al 1998 and Joshipura et al 2003). Periodontal microorganisms
had been found in atheromas (Haraszthy et al 2000 and Chiu 1999).The endotoxin in the
microorganisms could damage endothelial cells and induce smooth muscle proliferation (Lopes-Virella
and Virella 1985).
Figures 19 and 20 reveal no significant differences between control subjects with and without CI in
tooth loss and in PI respectively. This is not consistent with many previous studies (Syrajanen et al
1989, Mattila et al 1989.A, Mattila 1993, Kweider et al 1993, DeStefano et al 1993, Mattila et al 1995,
Joshipura et al 1996, Grau et al 1995, Beck et al 1996, Loesche et al 1998, Morrison et al 1999 and
Kozarov et al 2005). This discrepancy may be due to the small sample size of present research or some
other superimposing risk factors. Periodontitis is primarily caused by anaerobic gram-negative
bacteria and is episodic in nature with relatively short periods of exacerbation (Beck et al 1996). Periodontal pathogens can evade local host defense mechanisms and even daily procedures such as tooth
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brushing and chewing can induce transient bacteremia (Sconyers et al 1973) and frequently
leads to substantial systemic antibody response to specific periodontal pathogenetic
microbes and their endotoxins (Tolo and Schenck 1985). Such systemic effect of dental
infection is also reflected by increased activity of von Willebrand factor (Mattila et al
1989.V), a marker of endothelial activation, and elevated leukocyte count and fibrinogen,
both risk factors for stroke and myocardial infarction (Kweider et al 1993). Periodontitis
was also correlated with leukocyte count and inflammatory markers and clotting factors
such as C-reactive protein (Noack et al 2001) which added much to their documented role in
atherogenesis.
4. 2. Carotid intima-media thickness and cerebral infarction:
Figure 29 reveals no significant association between IMT and CI in control group after
age matching. This may be due to the small sample size of present research, other
overlapping risk factors or it may suggest that, in present research population, the overall
increase in IMT of carotid artery is not shown to affect cerebral infarction. This is not
consistent with previous researches (Bots et al 1993.Ce, Polak et al 1993, O'Leary et al. 1999
and Chambless et al 2000). Based on a short follow-up period, O'Leary et al 1996, Chambless
et al in 1997 and Bots et al in 1997 showed that an increased common carotid IMT related to future
cardiovascular and cerebrovascular events. The internal carotid artery carries the blood supply of the
brain tissues and any lesion that constricts or blocks this artery will certainly interfere with cerebral
perfusion so, carotid atherosclerosis may be a site for occlusion, embolization, or clot formation (The
Asymptomatic Carotid Atherosclerosis Study Group 1989, O'Leary et al 1992 and Viereck et al 2005).
Several previous cross-sectional studies have shown that increased carotid intima-media thickness may
be of use as a marker of atherosclerosis elsewhere in the arterial system (Bots et al 1993.Ca, Polak et al
1993 and Bots et al 1994, who stated that "there is a growing belief that carotid intima-media thickness
(IMT) can be regarded as an indicator of generalized atherosclerosis"). This
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proposed "generalized atherosclerosis" is a unanimous risk factor for CI (McSween and
Whaley 1992). In an animal model study, diffuse cerebral ischemia from carotid occlusion
caused infarction only in the striatum, and a possible toxic effect of dopamine release in the
ischemic zone has been assumed to be related to the damage (Weinberger et al 1995). The
similar mechanism might be involved in human diffuse cerebral ischemia. However, in
another study CI in the basal ganglia were just as frequent on the contralateral side of the
arterial lesions as they were on the ipsilateral side of the carotid lesions, challenging the
assumption that carotid artery lesions caused these CI (Uehara et al 1999). Thus, an
alternative explanation is needed. Sise et al noted that CI were commonly found in these
patients who underwent carotid endarterectomy, but were found on the contralateral side of
the target carotid artery in more than half of the cases (Sise et al 1989). They suggested that
carotid plaque formation and small vessel thrombotic events were most likely parallel
phenomena related to the risk factors. Longstreth et al in 1998 and Shimada et al in 1990
analyzing restricted subjects with lacunes affecting only 1 side of the brain in a populationbased study, reported that the correlations of stenoses were not consistently stronger for
ipsilateral than for contralateral lacunes. It is interestingly observed that, in present research,
there are significantly higher CI% in subjects with ≥50% than in <50% degree of stenosis (figure 30)
and in subjects with markedly irregular to ulcerated plaque surface than in smooth to mildly irregular
plaque surface (figure 31), while there is no significant association between plaque texture and CI%
(figure 33) which are consistent with previous studies (Longstreth et al 2002) and may be related to the
pathogenesis of atherosclerotic lesion. It is noteworthy that there are no significant differences in IMT
between markedly irregular to ulcerated and smooth to mildly irregular plaque surface, and between
homogenous and heterogeneous plaque texture after age matching (figures 32 and 34 respectively)
which means that the already observed associations
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with CI% are due to these plaque characteristics rather than due to the overall
increase in IMT.
The presence of CI had been linked to carotid stenosis (Nicolaides et al 1993,
Hougaku et al 1994 and Brott et al 1994) and ulcerated carotid plaque (Nicolaides
et al 1993 and Hougaku et al 1994). Manolio et al in 1996 found that carotid
stenosis of 50% to 74% was associated with a threefold increased risk of stroke. A
lesser, but still significant association was observed with milder degrees of carotid
stenosis. Uehara et al in 1999, found that carotid artery stenosis was a significant
and independent predictor of CI in the basal ganglia. This finding was consistent
with the findings of other reports (Hougaku et al 1994, Shimada et al 1990, Norris
and Zhu 1992). In studies of symptomatic lacunar infarction, it had been pointed
out that ipsilateral carotid stenotic lesions were potential embolic sources
associated with lacunar infarction in the distribution of deep perforating arteries
(Pullicino et al 1980 and Horowitz et al 1992). Ghika et al reported that 28 of 100
patients with symptomatic lacunar infarction in the territory of the deep
perforators of the carotid system had ipsilateral carotid artery stenosis. Stenotic
lesions of the internal carotid artery may also play a role in the pathogenesis of
lacunes through hemodynamic effects (Ghika et al 1989). Similar to the previous
findings, the results of Brott et al showed that CI in asymptomatic carotid stenosis
were not uncommon but were evenly distributed ipsilaterally and contralaterally
to the stenotic artery (Brott et al 1994).
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4. 3. Conclusions:
It is concluded from the available data of present research that the
interrelationships between intima-media thickness (IMT) of carotid artery,
cerebral infarction (CI) and some of their risk factors are shown to be:
Direct progression of IMT with age, plasma concentrations of low density
lipoproteins (LDL), triglycerides (TG) and total cholesterol (TC) and with
periodontal index (PI) and the number of missing teeth and inverse relation
with plasma concentration of high density lipoproteins (HDL).
Strong relations between IMT and smoking, diabetes mellitus (DM),
hypertension (HT) and hypothyroidism (HO).
No relation between IMT and gender, aspirin intake, hyperlipidemia (HL) and
serum creatinine.
Strong relations between CI and smoking, DM, HT, HL, HO and aspirin
intake.
No relations between CI and gender, number of missing teeth, PI and serum
creatinine.
No relations between CI and the overall carotid IMT and plaque texture
characteristics.
Strong relations between CI and the degree of carotid stenosis and plaque
surface characteristics.
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4. 4. Recommendations:
Successful efforts to bring atherosclerosis under control were undertaken including
reduced cigarette smoking, altered dietary habits with reduced consumption of cholesterol
and other saturated animal fats, better control of hypertension, and improved methods of
treatment of nonfatal myocardial infarcts. Cigarette smoking is a dangerous health threat.
It is the origin of a habit which is generally lifelong persistent. This habit gains greater
significance with age, as the individual becomes more vulnerable to the effects of cigarette
smoking. There is no place for smoking in childhood, or for that matter at any age; hence
cigarette smoking should be discouraged on a community-wide basis. "Smoking is not
smart" campaigns, mounted on a peer level within the schools, can be beneficial to this end,
but only if they are repeated routinely not done as an isolated community project. The ready
availability of cigarettes also makes the habit easy to acquire. Another suggestion is to make
smoking prohibited in public buildings. The higher the levels of HDL, the lower are the risk
of ischemic heart disease. Hence, there is a great interest in dietary methods of lowering
serum LDL and raising serum HDL. Nondietary influences may also affect the level of blood
lipids. Exercise and moderate consumption of ethanol both raise the HDL level, whereas
obesity and smoking lower it. Periodontal care is a must despite the innocent behavior of
periodontal diseases in present study sample. Aspirin prescription must take in
consideration the increasing evidence of its adverse effects. Lastly, it has long been known
that physical activity, even in the elderly, lowers the risk for stroke. Significantly, a relatively
low level of exercise, such as walking, was sufficient to produce this effect. This modifiable
risk factor, often under-emphasized in elderly populations, provides a relatively
straightforward way to reduce stroke risk. Further comprehensive researches are suggested
to overcome the impact of small population size on many effects of risk factors.
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‫أية جممو ٍ‬
‫صنف املشاركون إىل مخس جمموعات‪ :‬جمموعة السيطره (أولئك الّذين ال ينتمون إىل ِ‬
‫عة من اجملموعات‬
‫األربع األخرى) وجمموعات السكري وفرط الضغط وفرط الشحوم وهبوط الغده الدرقيه‪.‬‬
‫وجدت عند غرياملدخنني يف جمموعة السيطره عالقات قويه ومعنويه بني ‪IMT‬والعمر و ‪LDL‬و ‪HDL‬و‬
‫‪TG‬و‪ TC‬و‪ PI‬وعدد األسنان املفقوده فيما مل تكن كذلك عند املدخنني‪ .‬و بعد تسوية العمر كان ‪IMT‬‬
‫أعلى مبعنويّه عند املدخنني من غري املدخنني‪ .‬كذلك كان ‪ IMT‬أعلى مبعنويّه عند بقية اجملموعات (عدا‬
‫جمموعة فرط الشحوم) منه يف جمموعة السيطره‪.‬‬
‫كما وجد أبن العمر أعلى مبعنويّه يف جمموعة األشخاص الّذين لديهم إحتشاءاً دماغياً منه يف جمموعة األشخاص‬
‫الّذين ليس لديهم إحتشاءاً دماغيا‪ .‬وكانت نسبة األحتشاء الدماغي (‪ )CI%‬أعلى مبعنويّه عند املدخنني‬
‫ومتناويل األسربين ومرضى السكري وفرط الضغط وفرط الشحوم منه يف اجملموعات املقابله‪.‬‬
‫مل خيتلف األشخاص الّذين لديهم إحتشاءاً دماغياً مبعنويه يف ‪ IMT‬عن جمموعة األشخاص الّذين ليس لديهم‬
‫إحتشاءاً دماغيا ولكن (‪ )CI%‬كانت أعلى مبعنويه عند درجات التضيق العايل وسطوح الصفائح التصلبيه‬
‫غرياملنتظمه منه يف اجملموعات املقابله‪.‬‬
‫بقية املقارانت املتعلقه ابجلنس وكرايتنني املصل مل تكن معنويه‪ .‬و يستنتج أب ّن العمر والتدخني وتراكيز‬
‫شحوم البالزما وأمراض السكري وفرط الضغط وفرط شحوم الدم وتناول األسربين كانت عوامل‬
‫املخاطره القويه ┘ ‪ IMT‬و ‪ CI‬وأ ّن األحتشاء الدماغي يرتبط ابخلصائص األسوأ ┘ ‪ IMT‬وليس‬
‫مبجمل الزايدة يف ‪ IMT‬ويقرتح القيام بدراسات أوسع وأمشل لتفادي أتثري صغر العيّنه على النتائج‬
‫غري املفسره‪.‬‬
‫‪H‬‬
‫‪E‬‬
‫‪B‬‬
‫أخلالصه‬
‫أكمل ‪ 362‬شخصاً (منهم ‪ 184‬ذكراً و ‪ 178‬أنثى) كافة متطلبات البحث احلايل اليت تضمنت صور الرنني‬
‫املغناطيسي للدماغ (‪ )MRI‬وفحص الشراين السبايت املشرتك والداخلي أبمواج دوبلرفوق الصوتيه وفحوصات‬
‫األسنان واللثه وفحوصات سريريه وحتليالت خمتربيه مع بعض املعلومات عن اجلنس و العمر والتدخني وتناول‬
‫األسربين‪.‬‬
‫أجري فحص صور الرنني املغناطيسي للدماغ للتعرف على وجود اإلحتشاء الدماغي (‪ )CI‬بغض النظر عن‬
‫مكان أو عدد أو حجم مخجات أإلحتشاء ضمن أنسجة الدماغ‪.‬‬
‫أجري فحص أمواج دوبلرفوق الصوتيه لقياس مسك وبعض خصائص الطبقتني الداخليه والوسطى (‪)IMT‬‬
‫للشراين السبايت املشرتك والداخلي األمين واأليسر(‪ CCA‬و ‪ ICA‬على التوايل) و كانت اخلصائص‬
‫املدروسه هي درجة التضيق )‪ )degree of stenosis‬و سطح و بنية الصفيحه التصلبيه ‪plaque‬‬
‫)‪ ) surface and plaque texture‬مع اعتماد املنطقة األمسك و اخلصائص األسوأ عند تعددها‪.‬‬
‫فحوصات األسنان واللثه مشلت تقصي األسنان املتبقيه حلساب األسنان املفقوده و سرب ما حول األسنان‬
‫حلساب دليل ما حول األسنان (‪ )PI‬والّذي ميثل معدل إحنسار إرتباط اللثه كمقياس لتدهور حالة اللثه‪.‬‬
‫ألفحوصات السريريه والتحليالت املرضيه مشلت قياسات ضغط الدم اإلنقباضي (‪ )SBP‬واإلنبساطي‬
‫(‪ )DBP‬وسكر الدم اإلمساكي (‪ )FBS‬وكرايتنني املصل(‪)serum creatinine‬وحملة الشحوم ( ‪lipid‬‬
‫‪" )profile‬ابلذات الشحوم الربوتينيه واطية الكثافه (‪ )LDL‬والشحوم الربوتينيه عالية الكثافه (‪)HDL‬‬
‫وثالثي الغليسرييد (‪ )TG‬والكوليسرتول الكلي (‪ ")TC‬و تقارير األطباء الإلختصاصيني ابلنسبة ملرضى هبوط‬
‫الغدة الدرقيه‪.‬‬
‫‪E H B‬‬
‫ِ‬
‫ِ‬
‫ِ‬
‫الرمحَ ِن ال َّرحيمِ‬
‫ِ‬
‫هللا‬
‫سم‬
‫ب‬
‫ّ‬
‫بل الوريدِ‬
‫ِ‬
‫ح‬
‫َ َ‬
‫صد َق هللاُ العلِ‬
‫الع ِظ ُيم‬
‫ي‬
‫ََ‬
‫َ ُّ َ‬
‫‪BACK‬‬
‫‪HOME‬‬
‫‪EXIT‬‬
‫ألعالقة بين احتشاء الدماغ وتصلب الشريان السباتي مع بعض عوامل‬
‫المخاطره‬
‫رساله مقدمه اىل كلية الطب ‪ /‬اجلامعه املستنصريه كجزء من إكمال متطلبات‬
‫درجة الدكتوراه يف الفسلجه‬
‫للطالب‬
‫ابسم متعب هادي زوين‬
‫إبشراف‬
‫بسام طالب الكيالين‬
‫أ‪.‬د‪ّ .‬‬
‫‪BACK‬‬
‫الشماع‬
‫حممد حسن‬
‫ّ‬
‫أ‪.‬د‪ .‬يسار ّ‬
‫‪HOME‬‬
‫‪EXIT‬‬
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