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The Pathogenesis of Atherosclerosis

By: Margaret Banning BSc (Hons) MSc PGDE SRN SCM

This 2.0 Contact Hour Educational Design II program is presented by the Stony Brook School of Nursing, which has been
approved as a provider of Continuing Education by t he New York State Nurses Associations Council on Continuing
Education, which is accredited by the American Nurses Credentialing Centers Commission on Accreditation.
It has been assigned Code 4FEQ5U-PRV-2022.

Description:
Problems that result from the effects of Atherosclerosis may be attributed to some causes of death in
Western societies. In specifically, it may well account for over 50% of the mortalities in the UK and
the USA which at a estimate may be circa 500 individuals / day or 170,000 annually.

It is a disease that involves the circulation of low density lipoproteins within the blood stream, these
eventually accumulate in the cell wall of large and medium sized arteries to form plaques or
atherosclerotic patches which later inhibit the flow of blood. Stasis of blood promotes clot formation
which can be lethal to major organs in particular the heart and cerebrum. Prevention of lipid-
mediated changes to arterial structure can only be achieved through dietary modification or lipid
modifying drugs. The ultimate goal for nurses is to help reduce the incidence of heart disease through
appropriate health education.

Purpose: To examine the pathophysiological concepts pertinent to the development of
atherosclerosis and its consequences
Leani ng obj ect i v e s: By the completion of this educational programme the student should be able to undertake the following:
By the completion of this educational programme the student should be able to undertake the following:
1. Discuss the epidemiological evidence thought to be related to the development of atherosclerosis
2. List the risk factors associated with the development of atherosclerosis
3. Describe the changes that occur in atherosclerotic arteries
4. Identify the role of lipoproteins in the development of atherosclerosisIndicative content


Content Outline:

Epidemiological evidence which supports the demographic details of the prevalence of
Atherosclerosis.
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Explore the groups of individuals who may be at risk of developing Atherosclerosis
Pathogenic changes to the arterial cell structure
Role of lipoproteins in the development of Atherosclerosis
Genetic influences to the development of Atherosclerosis
Response to injury hypothesis
Oxidation hypothesis
LDL receptor hypothesis
Myocardial infarction and its consequences
Role of the nurse as a health educator

Atherosclerosis is a major cause of death with atherosclerotic lesions isolated in large and medium
sized arteries, the brain, the heart and the legs. Stary et al., (1984) offered the first evidence that the
development of atherosclerosis was a multifactorial process that commenced during childhood
(Mohler, 2000). The process involves the macrophage that develops into a foam cell is deposited
within the junction of the tunica intima and tunica medial layers of the artery during the first weeks of
life and later progresses into a fibrous atheroma from 30 years of age onwards (Napoli et al.,
1999). In 1984, Faggiatto & Ross, suggested that an association existed between the endothelial
cells and the macrophage. This relationship was later developed into the response to injury
hypothesis. Since this time, the pathogenic processes underpinning the development of
atherosclerosis remain conjectural.

Epidemiological evidence in support of the prevalence of atherosclerosis
Anand et al., (2000) examined the differences in risk factors for atherosclerosis and cardiovascular
disease in North Americans of European, Chinese and Southern Asian origin. Anand et al.,
assessed the prevalence of cardiovascular disease using the mean maximum intimal medial thickness
of coronary arteries as an indicator of the extent of carotid atherosclerosis. Cumulative data show
that Southern Asians had higher readings compared to equivalent data in European and Chinese
North Americans. This index may also be used as a marker for the presence of small plaques that
may progress to rupture and contribute to coronary occlusion and potential ischaemia (Chambless et
al., 1997).

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In addition, Canadians of Southern Asian descent presented with raised values for novel risk factors
such as plasma fibrinogen, plasminogen activator inhibitor 1, lipoprotein a and homocysteine. As
well as the highest serum level for glucose and plasma lipid abnormalities.

Evan though, the main assessment method used by Anand et al., may be classified as a novel index,
several criticisms of the method have been reported. Bell (2000) offers some generalisations
regarding the lack of clarity in the diagnosis with regard to Southern Asians, this mainly reflects the
fact that no correlation was made between the biochemistry data for Southern Asians and a
diagnosis of insulin resistance or metabolic syndrome. As Reaven et al., (1996) points out there is a
consistent pattern between high glucose level and insulin resistance in this ethnic sub-group.

An association between insulin resistance and endothelial dysfunction has been reported previously
and used to anneal the relationship between insulin resistance and ischaemic heart disease (Despros
et al., 1996). Given the fact that South Asians demonstrate a higher frequency of insulin resistance,
they represent an ethnic group that have multiple independent risk factors which reflect a higher
propensity to develop ischaemic heart disease (Mather & Keen, 1985, McCarthy, 2000)

Although, the benefits of examining ethnic subgroups within a population cannot be discouraged, the
application of many studies to the general population are limited due to the small sample sizes
involved. The main areas of concern which need to be pursued are not mutually exclusive to other
ethnic populations and include the control of modifiable risk factors; hypertension,
hypercholesterolaemia, and cessation of cigarette smoking can reduce fatalities (Levy & Kannel,
2000).

Role of lipoproteins in the development of atherosclerosis
Fats are water insoluble products complexed in saturated and non-saturated forms as triglycerides
and cholesterol. Fats are a source of energy and provide on circa 38% of the bodies metabolic
requirements for energy. The average intake of fats is circa 90-190 mg per day. In the Western diet
the ratio of saturated to polyunsaturated fats is about 0.3 which is considered low, an ideal ratio
would be >1.0, this can be achieved by reducing the quantity of consumed saturated fats to less than
15%.
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The average daily intake of cholesterol is about 300-500 mg much of this provision can be found in
animal products such as eggs. As the quantity of dietary cholesterol consumed can significantly alter
serum levels, it is therefore ideal to maintain the average intake of cholesterol to <300 mg / day.

There are two methods of maintaining adequate levels of triglycerides and cholesterol; an exogenous
source maintained by consumption of products that are of dietary origin and an endogenous source
produced from circulating free fatty acids (FFA) and glycerol synthesised from acetyl Co enzyme A
as part of Krebs cycle. This is a series of chemical reactions that occur in the liver, intestine, adrenal
cortex and skin.

Fats are transported between the intestine, liver and periphery in soluble complexes called
lipoproteins. These circulate in spherical particles and comprise an envelope of phospholipid and
apoproteins with a non-polar lipid core. Lipoproteins can be differentiated by density, configuration
and electropheretic mobility into chylomicrons, very low density lipoprotein (VLDL), low density
lipoprotein (LDL), intermediate density lipoproteins (IDL) and high density lipoprotein (HDL)
(Table 1).

It has been shown that the greater the concentration of LDL, the greater the risk of developing
atherosclerosis. The relationship between LDL and atherosclerosis is becoming clearer, with the
revelation of the structure, binding domains and the molecular pathways involved in the production
of modified LDL (Hevonoja et al., 2000). Receptor sites specific for LDL, take it up and degrade it
to form cholesterol, thus LDL is effectively removed from the serum. However, this response is
dependent on the quantity of LDL receptors available and the demand for cholesterol. So the
demand correlates with the supply of receptors. A reduction in available receptors, decreases the
removal rate of IDL within the circulation, allowing plasma the LDL concentration to rise and
atherosclerotic processes to accelerate.

Table 1. Reference range for blood lipids
Lipid Range (mmols/ L)
Plasma Cholesterol 3.5-6.5
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Low density lipoprotein 1.55-4.4
Very low density lipoprotein 0.128-0.645
High density lipoprotein/ triglycerides 0.5-2.1
Total lipid 4.0-10g / L


LDL is composed of a core of 1500 molecules of cholesterol enclosed in layers of phospholipid and
unesterified cholesterol molecules. The hydrophilic portions of the molecule are arranged on the
outside which allows LDL to dissolve in blood or extracellular fluid. A large protein called
apoprotein B-100 is embedded in this hydrophilic layer. This protein is recognised and binds to the
LDL receptor which spans the full thickness of cells plasma membrane in clusters within specialised
regions forming craters or indented areas referred to as clathrin coated pits. These pits pinch
inward to allow LDL to be carried into the cell. This process is called receptor mediated
endocytosis. LDL is recycled and used as necessary with excess LDL digested by lysosome. Even
though cholesterol is a precursor of mineralocorticoids, glucorticoids and sex hormones and the
quantity of these hormones produced are independent on LDL metabolism.

Cholesterol levels are controlled by enzymes responsible for its metabolic synthesis such as HMG
CoA reductase. If this enzyme is suppressed, the cell becomes dependent on a supply of cholesterol
from LDL. Alternatively, stored cholesterol is derived from LDL mediated processes using an
alternative enzyme system; Acyl CoA transferase (ACAT) which chemically alters cholesterol in
order to allow appropriate deposition of cholesterol in the form of storage droplets. However, the
most important mechanism involves the reduction in cholesterol synthesis by the cell reducing the
quantity of LDL receptor sites. Cells therefore adjust the number of receptors in order to meet the
demands of cholesterol but not the excesses. If the demand exceeds the supply, then an
accumulation of cholesterol will occur.

LDL is generated by the bodies fat-transport system via two mechanisms; the exogenous and the
endogenous pathways. The exogenous pathway begins in the intestine, and commences as the
dietary fats become packaged into lipoprotein particles called chylomicrons. These are large
particles composed mainly of triglyceride, synthesised in the small intestinal mucosa and transported
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from dietary fat.. Chylomicrons contain phospholipid, cholesterol, apolipoproteins (apo), for
example apo B48, apo A-1, apo 11, C 11 and apo-E. The presence of the apo-C-11 surface
protein activates the capillary endothelial enzyme lipoprotein lipase that is responsible for the
conversion of chylomicrons into chylomicron remnants or esters and VLDL. Both of these products
are then activated by apo C-11 and circulate in peripheral tissues to be later absorbed by hepatic
apo B and apo E receptors.

Triglycerides or the FFA are removed by lipolysis with the apo A-1, apo A-11, apo C transferred
to HDL. The liver and intestine are the major sites of HDL catabolism, this lipoprotein contains 25-
50% of the circulating cholesterol. HDL is the substrate for lecithin cholesterol acyltransferase
(LCAT) which catalyses the conversion of free cholesterol to the cholesterol ester which also
involves fatty acids. This esterification reaction involves the major proteins; Apo 1 & Apo 11.
Excess triglycerides can be transported to storage sites such as adipose tissue or muscle to supply
energy through oxidation

In contrast, the endogenous pathway begins when the liver secretes very low density lipoproteins
(VLDL) into the bloodstream. VDLs are the products of endogenous triglyceride synthesis within
the liver. They contain the apo B-100 and apo-E proteins which are catabolised by lipoprotein
lipase within peripheral tissues. VLDL upon reaching capillaries of adipose tissue or muscle extract
the triglyceride units leaving enriched cholesterol esters with two apoprotein units. VLDL upon
reaching capillaries of adipose tissue or muscle extract the triglyceride units leaving enriched
cholesterol esters with two apoprotein units. These are referred to as intermediate density
lipoproteins or IDL and are removed from the circulation about 2-6 hours after their formation.

VLDL are broken down with small apolipoproteins and transferred to HDLs which produce smaller
fragments or IDLs, these are taken up by hepatocyte LDL receptors facilitated by binding onto the
IDL surface apo E protein. IDLs can be converted to LDL through the hydrolysis of triglcyerides via
hepatic lipase. LDL is the major cholesterol carrying lipoprotein in normal plasma. They enter liver
cells by binding to high affinity receptors found in the clathrin coated pit region that recognises the
apo B 100 protein. Following binding LDL is internalised, metabolised and then releases free
cholesterol that partially contributes to the endogenous cholesterol level.
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Liver sinosoidal endothelial cells and macrophages act as scavenger pathways which aim to
consume available LDL via acetyl-LDL receptors, by absorbing LDL modified by oxidation. This
process converts macrophages into foam cells or primary lesions found in atherosclerotic arteries.

Genetic influences in the development of atherosclerosis
Numerous genes for 10 apolipoproteins and 4 lipoproteins have been isolated for chromosomes 1,
2, 3, 6, 8, 11, 15, 16 and 19, with the gene for the LDL receptor has been located on chromosome
19. Mutants of this gene have been associated with familial hypercholesterolaemia. This genetic
condition occurs in individuals who inherit a mutant gene or are heterozygotes and possess less than
50% of the required LDL receptors. Heterozygotes possess one normal gene but inherit a mutant
gene that contains the genetic code responsible for the LDL receptor protein. These individuals
synthesise about 50% of the usual quantity ofLDL receptors and can bind and degrade 50% of the
normal rate of LDL. Roughly, 1:500 people are affected by this mutation. Plasma LDL levels are
high, and a large proportion of patients will suffer from a cardiac incident by the age of 35 years. In
contrast, the homozygotes possess 2 mutant genes or possess a genetic predisposition to
hypercholestrolaemia. These inherited defective LDL receptor genes are both incapable of
synthesizing normal receptor and maintain an abnormally high LDL concentration due to an
increased production of LDL and decreased removal of LDL.

LDL and cholesterol levels can be used as biochemical predictors for the development of coronary
heart disease. The cholesterol deposits found in atheromatous lesions are derived from LDL as it
enters lesions by a rate-dependent response into the plasma concentration.

Response to injury hypothesis
Stated that the endothelium helped to regulate homeostasis of the cardiovascular system. This
proposal was supported by the fact that an intact endothelium is capable of releasing antithrombic
and fibrinolytic factors in addition to the potent vasodilator nitric oxide. In normal blood vessels,
nitric oxide and acetylcholine induce vasodilation, but with endothelium damage, disruption of cell
state negates normal function and the actions of potent vasodilators. The damaged endothelium
causes abnormal responses from acetylcholine by increasing the production of vasoconstricting
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agents such as thromboxane A
2
and prostaglandins. In addition to eliciting t he development of
abnormal intracellular signalling mechanisms which augment an increase in intracellular Ca
2+
and
endothelin-derived vasoconstricting factors.

Endothelial damage also triggers platelets to adhere and aggregate at the site of the damage, this enhances
monocytes to enter the tunica intima, and proliferation within the tunica-media junction of the artery. This
effect causes the arterial wall to herniate at this site. With increased monocyte invasion into arteries, and
continual herniation the lumen of the artery can become processively reduced. This combination of
biochemical and anatomical alterations contributes to oxidative stress and increased vascular damage; the
so-called precursors for atherogenic changes within arteries.

An increase in plasma cholesterol and its main transporter, LDl is an important risk factor in
atherosclerosis. One variant of LDL has an apoprotein which reduces fibrinolytic activity and can
induce thrombosis.

Oxidation hypothesis
The prerequisite for macrophage uptake and cellular accumulation of cholesterol is oxidative
modification of LDL (Witzum & Steinberg, 1991). The initiation of the oxidation process is induced
by the intracellular generation of lipoperoxides which are transferred to LDL through the
development of O
2
derived free radicals. These species later initiate a series of chemical reactions
that are generally referred to as lipid peroxidation. These chemical reactions are maintained by the
conversion of lecithin to lysolecithin catalysed by the plasma membrane bound enzyme
phospholipase A
2
. Lipid peroxidation contributes to the destruction of the lipid components of the
plasma membrane and enhances the release of fatty acids through fatty acid fragmentation and the
formation of the reactive intermediate species referred to as lipoperoxides. These overwhelm LDL
and are generated continuously by Cu
2+
ions in conjuction with peroxy radicals. Lipoperoxides are
toxic to plasma membranes as they re-arrange the chemical structure of the double bonds found in
fatty acids, they also combines with apo B and phospholipids to prevent LDL from binding to the
LDL receptor.

LDL can undergo acetylation to an oxidised form which is then unable to bind onto native receptors.
Oxidised LDL contains lysophosphatidylcholine this is a potent chemoattractant for macrophages
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(Kume et al., 1992). Lysophosphatidylcholine upregulates the expression of vascular cell adhesion
molecule such as ICAM-1 which is present within the endothelium and increases monocyte
adhesion. Available LDL uses the macrophage as a scavenge molecule, it binds onto and internalises
the LDL. Internalised oxidised LDL then inhibits monocyte motility. Macrophages that have
phagocytosed LDL are referred to as foam cells due to their lipid-like appearance on microscopy
(Quinn et al., 1987).

The LDL Receptor Hypothesis
In 1984, Brown & Goldstein suggested that high levels of LDL contributed to atherosclerosis as a
result of are due to down regulation of LDL receptors via apo B100 and failure of receptor
mediated endocytosis. Implying that LDL accumulated within the blood and could not be degraded
within the cell. This situation arises in patients with Familial Hypercholestrolaemia and in individuals
who consume a diet which is high in high in saturated animal fat. The continual exposure to a high
serum level of LDL has an inverse effect on the quantities of LDL receptors.

Factors Associated with Atherosclerosis

Cigarette Smoking
The metabolites of cigarette smoke are allylamine and the end product acrolein and reactive oxygen
species. It is thought that oxidative stress reduces the level of antioxidants available causing reduced
ability to inhibit lipid peroxidation, endothelial dysfunction in particular subendothelial oedema and
mitochrondial swelling (Zimmerman & McGeachie, 1987). The development of fatty streaks may
occur before endothelial cell denudation by a process involving severe cytotoxic changes to oxidised
LDL. Normally, oxidised LDL will aid the formation of a benign streak which then develops into a
complicated lesion. This adaptive change is enhanced by the altered function of the endothelial cell
which permits circulating monocytes to penetration into the intimal layers and act as a scavenger
receptor for oxidised LDL. The mature monocytes or macrophage after consuming oxidised LDL
forms a foam cell or a so called cholesterol clefts which acceleratee the formation of the fatty
streak. Smoking also increases platelet aggregation and the plasma concentrations of fibrinogen
which both contribute to the occlusion of arteries (Badimonet al., 1999).

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Diabetes
Hyperglycaemia contributes to interactions between endothelial functions producing abnormal
responses to acetylcholine, increased production of thromboxane and prostaglandins, raised
intracellular Ca
2+
all of which contribute to the release of endothelial vasoconstricting agents such as
acetylcholine and endothelin 1. The shunt in glucose to sorbitol via aldose reductase produces
fructose. Sorbitol enhances cell damage by augmenting cell swelling. Endothelium derived aldose
reductase contributes to highly abnormal cellular functioning and oxidative stress. Hyperglycaemia
also accelerates the generation of free radical mediated LDL oxidation (Kawamura et al., 1994).
Furthermore, available glucose can bind covalently to proteins by a process called glycation. This
process increases the production of free radicals causing glycoxidation, and glycative stress within
the cell, raises the quantity of glycated LDL and the athrogenic potential of LDL.

More recently, Schmidt et al., (1999) examined the role of pro-inflammatory mediators and their
contribution to the development of atherosclerosis in patients with an increased propensity to
develop Type 2 diabetes mellitus. The main findings showed that an increased risk was associated
with raised levels of acute phase proteins; orosomucoid,

-1, antitrypsin and haptoglobin, indicating

that autoimmunity may be a systemic factor in the development of both conditions.


Hypertension
Hyertension induces similar endothelial dysfunction by reducing Nitric Oxide (NO) mediated
vasodilation and increased vascular resistance (Panza et al., 1993). This may relate to increased
Ca
2+
by either reduced NO synthetase or excess production of oxygen derived free radicals which
inhibit NO production.

Fibrinogen
Fibrinogen is the precursor of fibrin which influences blood viscosity, flow and coagulation. Raised
levels promote platelet aggregation, fibrin and thrombi formation which stimulates cell proliferation
and plaque formation. These processes may also involve elevated levels of Factor VII and
plasminogen activator which can act as predictors of atherosclerosis (Cortellaro et al., 1993).

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Hypercholestrolaemia.
Small, dense LDL is more atherogenic than larger, buoyant forms. When accompanied by raised
triglycerides, reduced HDL, decreased LDL binding to apo-A1 occurs. Insulin resistance increases
the susceptibility to oxidation with HDL synthesised de novo within the intestine, liver, circulation or
peripheral tissues. Excessive levels of phospholipid or cholesterol attenuate the protective function of
HDL. As lipoprotein lipase positively correlate with HDL, low concentrations increase apo A1 &
II, catabolism reduces levels of available lipoprotein lipase and increases hepatic lipase leading to
hypertriglyceridaemia (Brinton et al., 1991).

Reduced levels of HDL-cholesterol
The predictive role of HDL may be to mediate hepatic excretion of cholesterol by reverse transport
to the periphery. Genetic factors known to contribute to low HDL-cholesterol concentrations
involve the following alterations:
a. genes for apolipoprotein A1-C11
b. Lipoprotein lipase
c. Cholesteryl ester transfer protein
d. Hepatic lipase
e. Lecithin-cholesteryl acyltransferase.

Harper & Jacobson, (1999) found that 11% of males in the US presented with low HDL-
cholesterol, a rationale for this level was unclear and still remains an enigma. In patients with a
history of familial HDL deficiency, the rationale for the disease may be a consequence of an
autosomal recessive disorder linked to key mutations found in the ATP-binding cassette (ABC1)
transporter gene, which encodes for cholesterol-efflux regulatory protein (CERP). Mutations in this
gene underpin the reduction in the quantity of protein and its functional activity and therefore
cholesterol transportation. This defect is common in the pathogenesis of Tangier Disease; a rare
disease diagnosed in about 40 patients world wide in which cholesteryl-ester disposition occurs in
several tissues and has also been isolated in 40% of cases of familial HDL deficiency (Macil, et al.,
1999).

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Trafficking of HDL in patients who have a deficiency of HDL usually present with cholesterol
depleted HDL particles that are rapidly catabolised and reduced cellular cholesterol efflux. This
disorder is an inborn error of metabolism and is referred to as familial HDL deficiency. Patients with
HDL deficiency are not usually diabetic and do not exhibit hypertriglyceridaemia but are likely to
present with an HDL-cholesterol concentration of 0.4-0.9mmol / L. The effects of deficient
production of HDL requires more research to evaluate fully the relationship to coronary heart
disease.

Pathogenic changes to the arterial cell structure
Affects large & medium-sized arteries. Lesions comprise fatty streaks, fibrolipid plaques and
complicated lesions (Table III).

Table II. Components of plaques
Tissue related components Biochemical components
Smooth muscle Calcium
Macrophages Triglycerides
Fibroblasts & fibrin Cholesterol
Elastin Phospholipids
Collagen & glycosaminoglycans Cholesterol esters


Myocardial infarction and its consequences
The fragility of atheromatous plaques has been related to their irregular formation and propensity to
rupture. Unstable atherogenic plaques have an increased tendency to rupture which can then
progress to an acute occlusion of arteries and develop significant conditions such as major organ
ischaemia as found in Myocardial Infarction or stroke. This form of pathological change is normally
associated with fissuring of the coronary artery plaques leading to spontaneous coronary dissection
and coronary embolism. Alternatively, rupture may result from iatrogenic causes such as coronary
artery bypass, catheter-based vascularization or local factors such as coronary artery artheroma or
superimposed thrombus or plaque haemorrhage (John et al, 1999). Atherosclerosis has multiple
consequences (Table III).

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Infarction is the ischaemic death or necrosis of tissue. Necrosis is the organised cell death of a tissue
and mainly involves inflammatory infiltration, leukocytosis and fibrous repair mechanisms following
the release of enzymes form the ischaemic tissue. Fuster et al., (1992) has shown that Myocardial
Infarction, myocardial ischaemic events and cardiac necrosis can result from the irregularity of
atheromatous plaques. Plaque instability have been associated with systemic factors such as
infection, involvement of a genetic predisposition, autoimmunity.

Table III. Potential complications of Atherosclerosis
Myocardial infarction Myocardial rupture
Cardiac arrhythmias Emboli formation

Cardiac failure Cardiac aneurysm
Mitral valve incompetence Ischaemic heart disease &
fibrosis

Numerous systemic variables have been investigated with the aim of developing some association
between plaque instability / rupture and the cardiac pathologies. The most commonly reviewed
factors examined involve; plaque anatomy, the relevance of sheer stress; the influence of
inflammation and haemorrhage (Touboul, 1994); pre-existing infection and the inflammatory
response (Danesh et al.,1997, Bosch, 1999).

Rothewell et al., (2000) examined plaque surface morphology of carotid arteries in patients with
history of myocardial infarction. Findings indicated that an association may exist between systemic
factors and the irregularities of surface morphology of carotid arteries, with local factors having only
a limited role in the development of acute coronary events. There findings also indicate that role of
traditional risk factors requires further analysis particularly in patients who present with smooth
plaques as these are considered stable and therefore less likely to rupture. Rothwell highlights the
value of systemic factors in their potential involvement in plaque irregularity, however, the lack of
clarity with regard to inferences with regard to the marginalization of traditional risk factors has led to
severe criticism. Meschia et al., (2000) reiterates that the contribution of genetic factors to the
fragility of atherosclerostic plaques does represent a true predisposition and is substantiated by
sufficient evidence (Cortellaro et al., 1992;1993). Moreover, Violi & Loffredo, (2000) cited in
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Meschia et al., (2000) present evidence to support the contribution of hyperlipidaemia to the
instability of atherosclerotic plaques. In doing so, they indicate that the potential for rising HDL-
cholesterol and lowering triglycerides offers protection against the progression of atherosclerotic
plaques. This value of this individual risk factor cannot be overlooked especially as associations have
been made with smoking and increased thrombogenicity (Badimon et al., 1999).

Cortellaro et al., (2000) cited in Meschia et al., (2000) criticises Rothwells findings on the basis of
the techniques used. He believes that current angiographic procedures are limited by their failure to
differentiate unstable from stable plaques, as both mural and endothelialised thrombi appear with a
smooth surface and cannot be distinguished otherwise (Arbustini et al., (1995, Bonn, 1999). It is
difficult to accept that Rothwell can do so without using alternative techniques and cannot support
the inferences made.

This is normally associated with fissuring of the coronary artery plaques leading to spontaneous
coronary dissection, coronary embolism. Iatrogenic cause (coronary artery bypass, catheter -based
revascularization) local factors Necrosis of heart muscle, usually left ventricle. Commonly due to
coronary artery atheroma & superimposed thrombus or plaque haemorrhage. Necrosis is the
inflammatory infiltration and fibrous repair. Enzymes released from necrotic muscle into blood,
leukocytosis.



Role of the nurse as a health educator
Nurses play an important role in the provision of education on how to improve the lifestyle of
patients through dietary modification and exercise. Dietary advice on how to lower cholesterol is
only one important aspect in the prevention of heart disease, particularly as this disorder is
multifactorial and is underpinned by multiple risk- and independent factors.

Dietary intake of cholesterol includes the contribution of animal fats found in red meat, cheese,
cream and whole cream milk and from cooking oils. Those oils that possess a high concentration of
saturated fats such as palmitic, stearic, myristic and lauric are known to be more athrogenic
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compared to the lower saturated fat based oils such as those containing oleic and lioleic acids. As
educators, nurses should be discouraging the use of cooking oils that possess higher levels of
saturated fats as these assist oxidation of LDL and foam cell formation (Table IV).

In an attempt to reduce the incidence of heart disease in the UK, manufacturers of margarine have
produced a range of products that aim to reduce serum cholesterol through modification of the
endogenous biochemical pathways (Mayor, 1999). One particular product in this range received
some criticism in that it does not reduce serum cholesterol in individuals who already maintain a
healthy diet (Heyningan, 1999). However, Thomson, (1999) suggests that these products are useful
for individuals at risk who do not adhere to a healthy diet, but fails to appreciate the financial
implications of purchasing expensive products for families who survive on low incomes. It is much
easier to reduce the risk of heart disease by dietary modification that does not involve the purchase
of expensive items.

In this regard, the consumption of fruit, vegetables and fish can be much more beneficial. By
encouraging patients to change the composition of their diet to include more oily fish such as
mackerel, trout and sardines. As these fish possess omega 3, 6 and omega 9 fatty acids which have
anti-atherogenic properties and therefore are of more benefit in the long term (Brown ,1999).

Table IV. The variety of cooking oils
Cooking Oil Type Common Examples
Oleic based oils Olive, safflower & sunflower oils
Linoleic based oils Seed oils; grape seed oil & walnut oil
Palmitic based oils Palm & cottonseed oils
Stearic based oils Lards & dairy fats
Myristic & Lauric based oils Coconut and palm kernel oils & dairy fats

It is well established that a high dietary intake of animal fat correlates with an increased incidence of
coronary atherosclerosis. In Japan and former Yugoslavia, dietary intake of animal fat appears to be
fairly minimal, therefore the incidence of atherosclerosis is not so widespread, whereas in Finland,
Northern Ireland and Scotland, the level of intake is high along with the incidence of coronary heart
disease. Animal fats are rich in saturated fatty acids that promote the accumulation of cholesterol.
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Rich animal fats have an inverse effect on the production of LDL receptors in the liver, so the
individual with a diet that is high in animal fat is increasing the risk of developing atherosclerosis. A
shift towards a Meditteranean style diet has been shown to be beneficial in the protection against
heart disease (Ruidaverts et al., 2000). This change in type of dietary advice should be beneficial in
the long term and hopefully help to prevent the development of atherosclerosis in children
(Ravnskov, 2000).

Some individuals are able to resist the increases in serum LDL concentration, irrespective of dietary
intake. Such individuals may possess inherited genes which allow them to circumvent the usual
feedback mechanism and maintain adequate LDL receptor levels. Diets have to be individualised in
order to try to maintain low saturated fat levels especially when there is a family history of heart
attacks or strokes. Science may produce drugs which aid the effects of diet-induced suppression of
LDL receptors.

The use of pharmacological methods to reduce cholesterol levels is used in patients that possess a
genetic predisposition to raised levels or have made serious attempts to reduce levels though diet but
have failed. Drug therapy aims to remove excess cholesterol from the circulation and is based on the
axiom that cholesterol is degraded into biliary acids by the liver. These acid then undergo entero-
hepatic recycling to be reabsorbed fromthe intestine into the bloodstream, are absorbed by the liver
and are secreted back into the upper intestine. By interrupting biliary recycling, bilary acids become
depleted and the liver converts more cholesterol into biliary acids and in so doing induces the
production of LDL receptors. Bile-acid resins such as cholestryamine, are positively charged and
bind to negatively charged biliary acids, so the chemical interaction produced encourages excreted
resins to carry bound acids with them. This process although, fairly effective only allows a 10%
increase in the quantity of LDL receptors on liver cells, as this is not sufficient to promote the
reductions in serum LDL required alternative drug therapies are utilised.

In these cases, the use of HMG Co-A-reductase inhibitors to reduce serum cholesterol has been
shown to be worthwhile and can help reduce the extent of further damage to the heart (Khong et
al., 1998). Patients admitted to coronary care normally have their serum cholesterol checked as part
of routine admission, if high patients should be targeted for therapy or dietary advice to reduce the
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level to a more acceptable value. Missouris & MacGregor (2000) evaluated the quantity of patients
receiving HMG Co-A-reductase inhibitors to reduce serum cholesterol levels on discharge from a
coronary care unit. Initially only 13% of patients were prescribed HMG Co-A-reductase inhibitors
on discharge. After developing a protocol that permitted coronary care trained nurses to prescribe
HMG Co-A-reductase inhibitors to patients on discharge, the quantity of patients receiving these
drugs increased to 89%. This small change in practice empowered nurses with more responsibility
and made some impact on the correct management of patient health (Holt et al., 2000). The value
of initiating this change will hopefully ensure that patients that are at risk of developing Ischaemic
Heart Disease such as Diabetics will benefit from drugs that aim to reduce serum cholesterol level
(Fowkes et al, 1998, McCarthy, 2000).
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CE Quiz:

Questions and Answers
Q1. Atherosclerosis may result from the occlusion of which of the following:
a. large arteries and medium sized arteries
b. small arteries
c. large veins
d. small veins


Q2. Which of the following ethnic subgroups have an increased propensity to develop Ischemic
Heart Disease:
a. Europeans and Southern Asians
b. Japanese
c. Mexicans
d. Chinese

Q3. Cholesterol and triglycerides can be packaged with a variety of proteins to form various forms
of lipoproteins. These include:
a. Very low density lipoproteins, High density lipoproteins, and Intermediate density lipoproteins.
b. Mixed density lipoproteins
c. Variable density lipoproteins
d. None of the Above

Q 4. Lipoproteins can be differentiated by the following:
a. Class and molecular weight
b. configurationand Density
c. electrophoretic mobility
d. B and C

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Q5. Chylomicrons contain which of the following apolipoproteins ?
a. apo B48, apo E and apo C-11
b. apo C48
c. apo D
d. None of the above

Q6. Lipoprotein lipase is the enzyme responsible for extraction of triglyceride from which of the
following lipoproteins ?
a. Chylomicrons and VLDL
b. IDL
c. HDL
d. LDL

Q 7. The gene for the LDL receptor has been located on which chromosome ?.
a. 1
b. 11
c. 6
d. 19
e. 16

Q8. The condensate from cigarettes that have been smoked induces which of the following
pathological changes :
a. swelling of mitochrondria
b. subendothelial oedema
c. denudation of the epithelial lining of arteries
d. oxidative stress within the cell environment
e. All of the above

Q9. Rupture of atherogenic placques can contribute to which of the following:
a. thrombosis
b. occlusion of arteries
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c. cardiac arrhythmias
d. myocardial infarction
e. A, B, and D

Q 10. Nurses may encourage patients to improve their lifestyle through health education programs
that address the following:
a. Encouraging low protein, high glucose diets
b. Smoking cessation programs
c. Encourage patients to exercise using a variety of methods
d. Provide dietary advice on fat intake
e. B,C and D

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