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Interrelationships Between Cerebral InfarctionAnd Carotid
AtherosclerosisWith 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. and Professor Dr. Bassam T.MF.
Al-Gailani Yesar MH. Al-Shammaa M.B.Ch.B.(Bag) M.B.Ch.B.(Bag)
Ph.D.(Leeds, UK) Ph.D.(Leeds, UK) START
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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 EXIT
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Supervisor Professor Doctor Yesar M.H. Al-ShammaaM.B.Ch.B.
(Baghdad), Ph.D. (Leeds, UK). Head Department of Physiology College
of Medicine University of Kufa
EXIT
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StudentBasim M.H. ZwainB.D.S. (Baghdad) M.Sc. Physiology
(Kufa)
EXIT
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ABSTRACTINTRODUCTIONSUBJECTS AND
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TITLEDEDICATIONACKNOWLEDGEMENTLIST OF CONTENTSLIST OF TABLESLIST
OF FIGURESLIST OF ABBREVIATIONSEXITHOMEBACK
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ALPHABETICALLYREFERENCESEXITHOMEAsBeBiBoBrCeDiFrGiGrHarHoKahKawKoLiMaMcOlPauRiSalShStTyViWiZhBACK
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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.
EXITHOMEBACK
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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. Al-Shamma'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
Al-Mustansiriya and the College of Medicine, University of Kufa to
provide me the chance of this study. Our last prey is "Deo
Gratias". EHB
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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.EHB
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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. EHB
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CHAPTER ONEIntroduction1. 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:EHBR
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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 Mnckeberg'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). EHBR
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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.EHBR
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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,
Tybjrg-Hansen et al 2005 and Seidelmann et al 2005). EHBR
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The currently favored theory and the one receiving the greatest
attention is the response-to-injury 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 atherosclerotic changes in experimental animals; the
naturally occurring disease of humans begins with some form of
nondenuding subtle injury. Circulating endotoxins, hypoxia products
derived from cigarette smoke, viruses and specific endothelial
toxins such as homocysteine (accounting for the premature and
severe atherosclerosis homocystinurics) could be involved, but
thought to be much likely are hemodynamic disturbances (shear
stress, turbulent flow) and adverse effects of
hypercholesterolemia, perhaps EHBR
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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 (Gmez-Muoz 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.EHBR
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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-
(TGF- ). 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- (TGF-),
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). EHBR
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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).EHBR
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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 EHBR
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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 3550mg/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 =9095mmHg (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 non-smokers. 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 B-cells 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 full age range
although there was a
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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 (Syrjnen 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 TWOSubjects 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 T2-weighted
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:
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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 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.Heterogeneous: Nonuniform echogenicity throughout
lesion.
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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:2. 4. 1.
Systolic and diastolic blood pressure:
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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
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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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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
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CHAPTER THREEResults3. 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 between IMT & CI themselves will be
highlighted.
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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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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
non-smokers (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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index (PI) are having significantly strong positive correlation
with IMT (r=0.74 and r=0.49 p
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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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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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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
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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 (p69
years). In that age group, the cumulative risk factors have made
the patients' condition so bad to differentiate between smokers and
non-smokers.
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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
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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
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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
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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.
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CHAPTER FOURDiscussion 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, Jrgensen 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, Jrgensen et al 1994, Davis et
al 1996 and Kobayashi et al 1997), other study had demonstrated
that age was a common risk factor for
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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).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
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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