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112 Chapter 6 Atherosclerosis and ischaemic heart disease
cholesterol and triglyceride, which gives rise to particles
of dierent size and density. A high triglyceride content
confers low density—as the triglycerides are delivered to
the tissues, the remaining higher density cholesterol-rich
particles are cleared by the liver.
We can identify four main types of lipoprotein whose
characteristics are summarized in Table 6.1. Note that in
clinical investigations the level of these dierent
lipoproteins in the blood will play a central role in
dening a therapeutic strategy, as illustrated in
Workbook 3.
1 Chylomicrons are large particles with a very high
triglyceride content and therefore very low density.
ey transport dietary lipids away from the intestines
to deliver them to muscle and other tissues for use as
energy sources. As chylomicrons pass through the
vascular beds of these tissues, the triglycerides are
freed by the action of lipoprotein lipase, an enzyme
located on the lining of the capillaries. e resultant
cholesterol-rich chylomicron remnants are cleared
from the blood by uptake into the liver. In this way
lipoprotein lipase activity contributes to the lowering
of blood total cholesterol. is in part explains the
benet of drugs which act to increase this enzyme’s
activity (see VLDL below, and Section 6.3.4). e
transport of lipids of dietary origin jointly by
chylomicrons and chylomicron remnants is termed
the exogenous pathway of cholesterol transport,
Table 6.1 Roles of different types of plasma lipoproteins
and their relative content of triglyceride/cholesterol
Lipoprotein
particle
Chylomicrons Transport
VLDL Exports
LDL Carries
HDL Returns
Role Triglyceride
content
+ + + + +
dietary fat
+ + + + +
cholesterol
and
triglycerides
from liver
+ + + +
cholesterol
to peripheral
tissues
+ + +
cholesterol to
liver
Cholesterol/
cholesterol
ester content
reecting the dietary origin of the cholesterol being
carried (exogenous—meaning coming from outside
the body).
2 Very low density lipoprotein (VLDL) provides the
transport mechanism in the blood for triglyceride and
cholesterol exported from the liver to the tissues. e
liver is at the centre of cholesterol regulation, receiving
this essential lipid in the form of chylomicron
remnants, as well as being the main site of its de novo
synthesis. e major drugs used to prevent
atherosclerosis (the statins, Section 6.3.2) inhibit
cholesterol synthesis. Triglycerides and cholesterol in
excess of the liver’s own needs are exported into the
blood in the form of VLDL, the rst step in the
endogenous pathway of cholesterol transport. VLDL,
like chylomicrons, is acted upon by lipoprotein lipase
expressed on the surface of the capillaries, which
hydrolyses their triglyceride content. e fatty acids
released are taken up by the tissues for fuel, leaving
higher density, cholesterol-containing particles—low
density lipoprotein (LDL). Drugs which act by
increasing lipoprotein lipase activity will therefore
facilitate the clearance of both VLDL and
chylomicrons from the blood (Section 6.3.4).
3 Low density lipoprotein (LDL) accounts for most of
the cholesterol found in the blood. It is this that
delivers essential cholesterol to the tissues.
Apolipoproteins on the surface of LDL particles are
recognized by specic cell surface LDL receptors. e
particle binds, and is then internalized into the cell by
the process of endocytosis. e resulting endosome is
acidied, releasing the cholesterol from the LDL inside
the cell to meet its needs. High levels of LDL result in
its deposition in various tissues, and it is here that we
see the link with atherosclerotic disease—excessive
uptake of LDL cholesterol from the blood into the
intima of the blood vessel plays a central role in
turning a healthy blood vessel into a dangerously
diseased one. is explains why LDL is referred to as
bad cholesterol.
LDL is also taken up by the liver through binding to
hepatic LDL receptors and subsequent endocytosis.
Increasing the number of these LDL receptors
enhances the clearance by the liver of circulating LDL,
and is a consequence of the action of a number of
lipid-lowering drug treatments (see below). In
familial hypercholesterolaemia there is an inherited
defect in LDL receptors, and this system of LDL
6.2 Atherosclerosis 113
uptake into the liver and other tissues fails. Suerers
have very high circulating LDL-cholesterol levels and
are at great risk of atherosclerosis and ischaemic heart
disease. Indeed, homozygotes for this condition
usually die in childhood from cardiovascular
disease.
4 High density lipoprotein (HDL), in contrast with
LDL, is sometimes referred to as good cholesterol. HDL
scavenges cholesterol from dying cells and delivers it
to the liver to be converted to bile salts or excreted.
is movement of cholesterol away from the tissues,
also called reverse cholesterol transport, explains why
plasma HDL is seen as benecial in maintaining a
non-atherogenic balance of cholesterol transport.
Some of the relationships between the dierent forms of
cholesterol circulating between the liver, intestines, and
other tissues are summarized in Figure 6.3.
Taking into consideration the roles of the various
lipoproteins described above, it is clear that high total
plasma cholesterol (TC) and high LDL-cholesterol are
undesirable. Lifestyle changes and drugs are aimed at
bringing down high levels of TC and LDL-cholesterol
while maintaining HDL-cholesterol levels, as explained
below. In Workbook 3, the normal levels of TC, LDLcholesterol, HDL-cholesterol, and triglycerides are set
out. ese are compared with levels in the patient Brian,
and this information is used to aid diagnosis, and to guide
his treatment plan.
6.2.2 Sources of circulating cholesterol
and the significance of bile
ere are two sources of cholesterol. One is dietary,
absorbed from the intestines and transported in
chylomicrons to eventually arrive in the liver. e other is
de novo synthesis in the liver.
Diet and bile
Bile is made continuously by hepatocytes and is secreted
into narrow channels which converge to form the bile
Liver
HMG-CoA
reductase
HDL
Bile salts
Chylomicron
remnants
VLDL
Cholesterol
Atheroma
Diet
Intestine
Lipoprotein
lipase
LDL
Chylomicrons
Triglycerides
Essential cell
cholesterol
Figure 6.3 Transport and inter-conversion of cholesterol.
In this simplified scheme, a central role is given to lipoprotein lipase, acting on the lipids as they pass through the vascular beds. See
Section 6.2.1 for an explanation of the events in this figure.
114 Chapter 6 Atherosclerosis and ischaemic heart disease
++→→
→
↑→
→→
duct which empties into the small intestine. Between
meals bile is diverted to the gall bladder for storage. e
presence of food in the small intestine triggers the
contraction of the gall bladder, which releases the bile
into the duodenum. Bile contains phospholipids and bile
salts which act as detergents to emulsify and solubilize
dietary fats, facilitating their absorption. Importantly, bile
salts are themselves derivatives of cholesterol and are
manufactured in the liver. Once the bile salts have
participated in fat absorption, they are actively
transported across the walls of the ileum and returned to
the liver via the hepatic portal vein, to be recycled. is
recycling pathway for bile salts is called the enterohepatic
circulation. A small amount of bile salts (~5%) are lost in
the faeces, to be replaced by new molecules synthesized
from cholesterol in the liver. Inhibiting bile salt
reabsorption, and favouring loss in the faeces, may
therefore be expected to reduce uptake of dietary
cholesterol due to impaired absorption from the
intestines. In addition, newly synthesized cholesterol will
be diverted into bile salt generation to replace that which
has been lost. is will reduce the output of cholesterol
from the liver in the form of VLDL, and thereby contribute
to reduced circulating plasma levels.
Cholesterol synthesis
e liver is the major site for cholesterol biosynthesis,
although some is also formed in the intestines. Synthesis
proceeds via a series of reactions which can be
summarized as follows:
acetyl CoAacetoacetyl CoA
[1]
hydroxymethylglutarylHMG -CoA
mevalonicacidcholesterol
Step [1] is the committed rate-limiting step in the
synthesis of cholesterol and is dependent on the
enzyme HMG-CoA reductase. The amount and activity
of this enzyme is highly regulated, with rates of
synthesis of cholesterol varying widely depending on
its availability in the diet. If this enzyme is inhibited
(see below), the liver will compensate by reducing its
output of cholesterol in the form of VLDL, and by
scavenging more cholesterol from the circulation by
increasing its uptake of LDL.
Atherosclerotic plaque formation
e generation of an atheroma on the inner face of a
blood vessel wall is a slow process, developing over years
→→→→→→
()
or decades without symptoms. It is initiated with
compromised endothelial function, progressing with the
incorporation of cholesterol and inltration of white
blood cells, establishing a chronic inammatory
condition of the vessel wall (see Box 6.1 for more detailed
description of the steps in atherogenesis).
As plaque formation proceeds a calcified cap develops
(see Box 6.1), which is particularly ominous since from
here a catastrophic sequence of events can rapidly
escalate. An individual may be unaware of an atheroma
until the calcified surface cracks, the plaque ruptures,
and a thrombogenic surface is exposed to which
platelets can adhere and become activated (see
Chapter 4):
calcificationoffibrous plaque rigidity andfragility
susceptibletorupture exposure of thrombogenic
surfacetocirculating blood foci forthrombus
formationfragmentation of thrombus emboli
rombus formation may quickly follow, leading to rapid
occlusion of the blood vessel. Alternatively, part, or all of
the thrombus may break free, forming an embolus or
emboli, which can travel and block further blood vessels.
ese are the events that underlie the onset of unstable
angina and MI.
Atherosclerosis typically occurs in large or medium-sized
arteries, but not all are equally susceptible. For example,
the internal mammary artery is normally free of
pathology in a patient with ischaemic heart disease, and
so this vessel can be utilized as a donor artery in bypass
surgery. is dierence in susceptibility between arterial
vessels is likely to be due in part to variation in blood
pressures, turbulence of ow, and shear forces, all of
which damage endothelium and are exacerbated by
hypertension.
Atherosclerosis as an inflammatory disease
Inammation (see introduction to Part 3) has been
established as part of the atherosclerotic process.
However, the standard anti-inammatory drugs
described elsewhere in this book have no role in
prevention or management of atherosclerosis. ere are,
though, indications that some of the drug treatments
referred to below may derive part of their therapeutic
benet from an inhibition of vascular inammation as
evidenced, for example, by clinical observations of a fall
in plasma C-reactive protein (CRP).
→
→→
→→↑
→→
→
→
Box 6.1
LDL
Monocyte Monocyte
Steps in atherosclerosis
e development of an atherosclerotic plaque progresses via a series of steps, conventionally described as shown
in Figures a, b, c, and d.
Blood
Area of damage
to endothelial lining
Tunica
intima
Tunica
media
Figure a
1) Injury to endothelial lining (caused, for instance,
by hypertension, elevated LDL-cholesterol, or
smoking-derived toxins) disrupts endothelial cell
functions such as NO production, which protect
against atheroma formation.
2) LDL-cholesterol crosses the endothelial barrier
to accumulate within the intima where it is oxidized
modified LDL (mLDL).
T lymphocyte
Inammation
mLDL
Foam cellMacrophage
Figure b
3) Expression of monocyte adhesion molecules by
dysfunctional endothelial cells, together with the formation
of mLDL, attracts monocytes into the tunica intima;
monocytes transform and become macrophages.
4) Macrophages and injured endothelial cells generate free
radicals that further oxidize LDL.
5) Macrophages scavenge mLDL and become large foam cells
which form fatty streaks.
Calcied
brous cap
Smooth muscle
cells migrate
and proliferate
adhesion
molecule
Collagen,
elastin
Figure c
6) T-lymphocytes and other inflammatory cells infiltrate the
diseased wall, establishing a chronic inflammatory
condition. Pro-inflammatory cytokines and growth factors
are released, promoting further LDL-cholesterol uptake
and white blood cell infiltration. Markers of inflammation
such as hepatic C-reactive protein (CRP) are increased.
Figure d
7) The plaque grows and matures, with migration and
proliferation of smooth muscle cells from the underlying
tunica media. Extracellular matrix proteins such as collagen
and elastin are deposited, calcium accumulates, and a
fibrous calcified surface (cap) develops.
116 Chapter 6 Atherosclerosis and ischaemic heart disease
6.3 Preventing atherosclerosis: lipid-lowering drugs
6.3.1 Thresholds and targets depend on
the patient
Patients with high total cholesterol are at increased risk of
cardiovascular disease. In such individuals, lifestyle
changes to reduce risk factors must always be undertaken
rst, since they have the greatest potential benet. ese
involve healthy eating, regular exercise, reducing alcohol
intake, stopping smoking, and stress reduction. Where
this approach is inadequate it can be supplemented by
drug treatment, which is then likely to be long term.
Before initiating treatment, hypothyroidism should be
ruled out as a reversible cause of dyslipidaemia.
Importantly, high LDL-cholesterol and low HDLcholesterol correlate with high risk, since LDL-cholesterol
accounts for the majority of circulating cholesterol; such
patients have high total cholesterol (TC) levels. In
practice, the most common objective of preventative drug
treatment is to lower TC and LDL-cholesterol. ere is,
however, recognition that raised HDL-cholesterol is
desirable. In addition, high triglyceride levels predispose
to ischaemic heart disease, and may be targeted by
certain drugs (see below).
e decision to commence drug treatment will be based
on whether TC and LDL-cholesterol have reached
threshold levels. It will also depend on the target levels for
the individual patient. Both thresholds and targets will
vary greatly depending on a number of factors and
importantly where, for instance, there is a prior history of
ischaemic heart disease or comorbidities such as
hypertension or type 2 diabetes. Smoking history, sex,
age, and race also need to be taken into account. Help is
conveniently provided by rapidly collating such
information into an integrated risk factor, using
algorithms such as those provided in many prescribing
guides. It is also worth noting that there is some variation
in targets and guidelines between countries.
While thresholds and targets are variable, the objective is
always to lower circulating levels of TC and LDLcholesterol. In the UK, as a starting guide, we note that after
modications to lifestyle, patients with TC >4 mmol/l, will
be considered for treatment. In addition, guidelines may
recommend that patients at higher risk of atherosclerosis
are prescribed lipid-lowering drugs regardless of starting
lipid levels. is may include individuals with established
cardiovascular disease (e.g. a history of angina), or those
with type 2 diabetes, or where there is a family history of
premature cardiovascular disease. In such patients, where
TC is >4 mmol/l, or LDL-cholesterol >2 mmol/l, more
aggressive treatment may be required. In the case of Brian
(Workbook 3), we see from his clinical clerking that he has
a TC of 9.2 mmol/l and an LDL-cholesterol of over
8 mmol/l, together with a history of cardiovascular disease
(stroke, in his case). From the account given above of the
central role for LDL-cholesterol in development of
atherosclerosis, we can understand the way in which these
circulating lipids have interacted with and damaged his
coronary artery walls over the preceding years, ultimately
leading to heart disease. e decision is made to proceed
with aggressive drug therapy to treat Brian’s dyslipidaemia,
with recommended targets of <4 mmol/l TC and <2
mmol/l LDL-cholesterol.
Four dierent pharmacological approaches to controlling
blood lipids with drugs can be identied according to the
major mechanism of action thought to contribute to their
therapeutic eect:
1) inhibition of cholesterol synthesis
2) reduction of absorption of cholesterol from the
intestines
3) elevation of lipoprotein lipase activity
4) elevation of circulating HDL.
Each category is represented by commonly prescribed
drugs. It is important to consider the mechanism of action
of these drugs to understand their clinical use, and why
certain combinations may be benecial in some patients.
6.3.2 Inhibition of cholesterol synthesis:
the statins
Statins are the rst-choice drug for the primary and
secondary prevention of cardiovascular disease and are
now amongst the most highly prescribed drugs in
industrialized societies. ey control plasma lipids by
inhibiting the enzyme HMG-CoA reductase, the ratelimiting step in cholesterol synthesis (Section 6.2.2). e
reduction in cholesterol synthesis encourages
hepatocytes to compensate by increasing their uptake of
circulating plasma LDL-cholesterol (Figure 6.4). is is
achieved through enhanced expression of LDL
receptors on the cell surface. e statins may therefore
be said to reduce circulating cholesterol by increasing
6.3 Preventing atherosclerosis: lipid-lowering drugs 117
Liver
HMG-CoA
Statins
Mevalonic acid
LDL
Cholesterol
Figure 6.4 Mechanism of action of statins.
Statins competitively inhibit the rate-limiting enzyme in cholesterol
synthesis, HMG-CoA reductase, leading to reduced hepatic cholesterol
concentration. To compensate, hepatocytes increase their uptake of
cholesterol from the circulation in the form of LDL-cholesterol.
LDL-cholesterol clearance. Indeed they are the most
eective lipid-regulating drug at lowering LDLcholesterol levels, although less eective than brates
(see below) at reducing triglyceride levels.
Cholesterol synthesis in the liver is at its peak in the early
hours of the morning. Statins with short half-lives, such as
simvastatin and pravastatin, must therefore be taken at
night for their inhibitory action to coincide with this
period. e drugs with longer half-lives, such as
atorvastatin and rosuvastatin, are eective for much
longer, and so can be taken at any time.
Statins are orally available drugs. ey are generally
eective as monotherapy; LDL-cholesterol can be reduced
by about 40% by high-dose simvastatin, and by over 50%
by atorvastatin. In patients whose response is not
adequate, greater reductions may be sought by using
statins in combination with other drugs acting by dierent
mechanisms, such as ezetimibe (see below). is is,
however, accompanied by an increased risk of side eects,
and for this reason statins are not combined with brates
(see below). Importantly, in the majority of patients statins
alone are the rst-option treatment to lower cholesterol.
In addition to the well-characterized eects on circulating
lipid levels, statins have a number of other potentially
benecial actions. Amongst those of clear therapeutic
benet are the following: antithrombotic eects including
enhanced brinolysis and inhibition of platelet aggregation;
improved endothelial function and vasodilatation; plaque
stabilization; attenuated inammatory processes as
evidenced by reductions in CRP levels. Some, but not all, of
+
these eects are explained by the inhibitory action of statins
on mevalonic acid synthesis. is molecule is an
intermediate not only in cholesterol production but also in
many additional biosynthetic pathways. No doubt the
clinical use of statins will be extended as our understanding
of these non-cholesterol eects develops.
Adverse effects of statins
Statins are generally well tolerated, but can have some
unwanted eects although these may be only mild and
transient; they include gastrointestinal disturbance and
headache. e potentially more serious eects are on
skeletal muscle (myopathy). ese are dose related, and
are more likely in certain patient groups, including the
elderly and those with hypothyroidism or high alcohol
intake. Muscle aching (myalgia), due to inammation of
the muscles (myositis), is usually resolved by withdrawing
the drug. Myositis with tissue breakdown
(rhabdomyolysis) occurs rarely, but can be serious.
Curiously, the risk of side eects is enhanced if a patient
takes grapefruit juice with the statin, as this contains
inhibitors of the hepatic cytochrome P450 enzymes which
metabolize the drug. is results in higher levels of the
statin in the body for longer. Risk of myopathy is also
increased when statins are taken alongside other
lipid-lowering drugs, such as brates or nicotinic acid
derivatives (see below), or with other drugs that inhibit
the hepatic P450 enzymes, including diltiazem,
amiodarone, amlodipine, and macrolide antibiotics.
Statins may lead to increased serum concentrations of
liver enzymes, and to jaundice and hepatitis, although
118 Chapter 6 Atherosclerosis and ischaemic heart disease
Resins
this is rare; they must be used with caution in patients
with hepatic impairment. e use of this drug class is
currently contraindicated during pregnancy because of a
perceived increased risk of congenital abnormalities.
6.3.3 Reduced absorption of cholesterol
from the gut: resins and ezetimibe
In the intestines, cholesterol is present both from the diet
and in the form of bile salts synthesized by the liver and
deposited into the duodenum (Figure 6.3). Reducing the
absorption of cholesterol from the gut therefore promotes
elimination from both these sources. To compensate for
the reduction in supply of dietary cholesterol, and in order
to meet its needs, the liver increases its absorption of
LDL-cholesterol, thereby further contributing to lowering
circulating cholesterol. We will consider two types of
agents that interfere with cholesterol absorption: the rst
is an old remedy which acts as a bulk absorber in the
intestines; the other is a newer, molecularly targeted drug.
Anion exchange resins in clinical use include
colestyramine and colestipol. ese bind bile salts in
the gut to form an insoluble complex which is then
eliminated in the faeces (Figure 6.5). By promoting the
loss of bile salts they act in three ways.
1. Uptake of dietary cholesterol is reduced due to
impaired absorption in the gut.
2. Newly synthesized cholesterol is diverted into
replacement bile salt production and consequently
cholesterol output from the liver is reduced.
3. Depletion of hepatic cholesterol upregulates the
expression of LDL receptors on hepatocytes,
promoting clearance of circulating LDL-cholesterol.
To have their eect, resins have to be consumed in bulk.
ey are unpalatable and may cause digestive problems,
and frequently lead to constipation. In addition they
interfere with the absorption of fat-soluble vitamins and
some drugs, including digoxin, warfarin, and thiazide
diuretics. ey are also associated with an unwanted
increase in triglycerides. For all of these reasons the use of
anion exchange resins is now limited. However, such
drugs do have a proven history of reducing LDLcholesterol levels and achieving a long-term reduction in
ischaemic heart disease. Also, since they are not absorbed
into the body, they play a role when other treatments may
be advised against (e.g. in pregnancy).
Ezetimibe is a more recently introduced small molecular
weight inhibitor specically targeted at blocking the
transport protein NCP1L1, responsible for the processing
Small intestine
Liver
BSCholesterol
+
Bile duct
–
LDL
HPV
BS
BS–resin
complex formed
Dietary
chol.
+
–
Figure 6.5 Mechanismofactionofanionexchangeresinsandezetimibe.
Bile salts, which are derived from cholesterol, enter the duodenum of the small intestine from the bile duct
and are actively reabsorbed across the wall of the ileum, to be returned to the liver via the hepatic portal
vein. Resins prevent this recycling of bile salts by binding them in complexes which are then lost in the
faeces. Resins also stimulate the uptake of LDL-cholesterol from the circulation. Ezetimibe inhibits the
absorption of dietary cholesterol by blocking its transport mechanism in the duodenum; amount of dietary
cholesterol reaching the liver as chylomicron remnants is therefore reduced. Effects of resins are shown in
blue, and those of ezetimibe in purple; solid lines, stimulation of processes; dotted arrows, inhibition of
processes. BS, bile salts; HPV, hepatic portal vein; LDL, low density lipoprotein.
Ezetimibe
Excretion
6.3 Preventing atherosclerosis: lipid-lowering drugs 119
Chylomicrons
and uptake of cholesterol across the gut wall (Figure 6.5).
It leaves the absorption of fat-soluble vitamins and bile
salts unaected. It is a potent drug, taken once a day;
combined with dietary advice, it has assumed an
important role in the management of high blood
cholesterols under two circumstances:
1) as an adjunct to statin therapy (see above) when
response is inadequate
2) As an alternative when statins are not tolerated.
e eectiveness of ezetimibe in reducing high LDLcholesterol is proven, yet its proper place in the treatment
of dyslipidaemia has not been settled. It is currently not
recommended as the rst option for either primary or
secondary prevention of ischaemic heart disease, yet it
remains quite widely prescribed.
Ezetimibe is administered by mouth and is generally well
tolerated, although reported adverse eects include
gastrointestinal disturbances, headache, fatigue, and
myalgia.
6.3.4 Elevation of lipoprotein lipase
activity: the fibrates
Fibrates are a class of drugs with complex eects on
circulating lipids that are only partly understood; they
combine to markedly reduce VLDL-cholesterol and
hence TC, whilst also resulting in a benecial rise in HDL.
In part, these eects are achieved through enhanced
expression of the lipoprotein lipase gene. As seen in
Figure 6.3, this enzyme has a central role in cellular
cholesterol trac. Fibrates activate a class of nuclear
(steroid) receptors, PPAR receptors, which serve as
transcription factors (see Chapter 2, Section 2.2.6) to
upregulate the expression of the gene encoding
lipoprotein lipase. e enzyme activity on the luminal
surface of the capillaries is thereby enhanced.
Figure 6.6 illustrates the mechanism underlying the major
clinical observation that brates reduce blood VLDLcholesterol and triglyceride levels. is decrease is
achieved in two ways.
1. Enhanced lipoprotein lipase activity increases the
hydrolysis of triglycerides from VLDL; the fatty acids
released are then taken into the tissues to be used as
fuel, or stored as fat.
2. Reduced secretion of VLDL by hepatocytes into the
blood.
e second clinical observation is that brates increase
circulating HDL, collecting cholesterol from the tissues
and returning it for reprocessing in the liver. As a
consequence of long-term remodelling of the cholesterol
trac, brates also bring about a reduction in LDLcholesterol. It seems reasonable to suggest that the overall
benet of brates to patients comes from the combined
eect on VLDL:LDL:HDL ratios.
Like statins, brates mediate a number of other benecial
eects, in addition to those on lipoprotein lipase; this eect
alone is not sucient to explain all the clinical observations.
Some of these additional actions arise from alterations in
the expression of other genes. For instance, it was
mentioned above that there is an inammatory aspect to
atherosclerosis. Fibrates decrease vascular inammation
TG
Chylomicron
Fibrates
Figure 6.6 Fibrates as lipoprotein lipase elevating drugs.
Increasing lipoprotein lipase activity within the vascular beds changes the balance of lipid
trafficking between the liver and the circulation. Solid arrows indicate an increase in
trafficking, the dotted arrow indicates a decrease.
Lipoprotein
lipase
remnants
LDL
TG
VLDL
Liver
120 Chapter 6 Atherosclerosis and ischaemic heart disease
(and CRP levels) by selective changes in anti-inammatory
gene expression which presumably contributes to the
clinical response. Additional benecial actions include
antithrombotic eects and enhanced brinolysis. It should
be noted, then, that brates can potentiate the anticoagulant
eects of warfarin, and caution must therefore be exercised.
Fibrates are used rst-line in the treatment of
hypertriglyceridaemia because of their eectiveness in
reducing these lipids. As they achieve only a moderate
reduction in LDL-cholesterol, they are not used rst-line
where LDL-cholesterol levels are high unless statins are
not tolerated, or are contraindicated.
Fibrates are usually well tolerated, but can have a rare, but
potentially serious, myositis eect, with muscle pain
associated with inammation and muscle cell
breakdown. Renally impaired patients are at greater risk.
Since myositis is also a side eect of statins, these two
drugs are seldom used together, and then only with great
caution. e combination of gembrozil and a statin
increases the risk considerably, and should not be given.
Elevation of circulating HDL: nicotinic acid receptor
agonists
Nicotinic acid (or niacin) has long been known for two
reasons: rst, it is an essential vitamin; secondly, in high
doses (1.5–3 g daily) it has a major benecial impact on
circulating lipids. While it does reduce circulating VLDL
and LDL-cholesterol, most interest in it has come from its
ability, more than the other drugs we have mentioned, to
raise HDL. Its mechanism of action, hitherto unclear, was
recently claried with the discovery of a nicotinic acid
receptor, which will help elucidate at least some of its
clinical eects. is raises the real prospect of new clinical
agents acting as agonists at this receptor to produce an
increase in circulating HDL.
Nicotinic acid has been shown to reduce the progression
of ischaemic heart disease and consequent mortality. It is
used as an alternative for those who cannot tolerate
statins, or as a partner to statins where the statin alone
cannot adequately control hyperlipidaemia. e
combination of the most eective LDL-lowering agent
with the most eective HDL-elevating agent seems a
marriage made in heaven. We look forward to the further
exploitation of this combination with the development of
new drugs in this class.
Adverse eects of nicotinic acid include gastrointestinal
disturbance, tachycardia, and palpitations. A limitation on
its use is that it very commonly causes profound cutaneous
vasodilatation (ushing), which leads to a large proportion
of patients (25–40%) discontinuing medication. e
vasodilatation is mediated by prostaglandin D2. It can
therefore be eectively reduced by the administration of
the cyclo-oxygenase inhibitor aspirin 30 min before
nicotinic acid is taken. It has also been reported that this
side eect is less pronounced with modied release
preparations, yet it still remains problematic. It is hoped
that future nicotinic acid receptor agonist drugs will be
free from this complication. In this respect acipimox, a
derivative of niacin,has a better side-eect prole, but is
less eective at lowering lipid levels.
6.4 Ischaemic heart disease: angina
When you run up a set of stairs your heart does more
work, and so its demand for oxygen increases. In a healthy
heart this increased demand is met by increased supply;
vasodilatation on the arterial side provides greater
perfusion of the heart muscle. Coronary blood ow can
increase sixfold during exercise compared with the
resting state. If, however, the coronary arteries are
partially occluded and their ability to dilate is
compromised, this increase in supply will be restrained,
resulting in supply not being able to meet demand. is is
ischaemic heart disease (Figure 6.2) and can result in
angina (pain or discomfort in the chest, neck, jaw, or
arms), or a myocardial infarction (MI) with death of heart
muscle tissue.
e severity of the ischaemic event will depend on:
1) the extent of the decreased blood ow
2) the duration of ischaemia
3) the rate at which the blood ow is reduced.
6.4.1 Coronary blood flow during systole
and diastole
Here we shall rst consider the nature of perfusion of the
heart during the cardiac cycle. (Some of these issues were
introduced in Chapter 5 when we considered
hypertension.) Remember that during systole the left
ventricle contracts and pressure within the ventricle rises
6.4 Ischaemic heart disease: angina 121
until it exceeds the pressure within the aorta—only then
does the aortic valve ip open and blood ow from the
heart (Chapter 5, Figure 5.6). At the peak of systole, the
pressure in the coronary arteries is lower than the
pressure within the ventricular tissue, and so coronary
blood ow falls. Paradoxically, coronary blood ow is
greatest during diastole, when aortic pressure is lowest.
is pattern of events is illustrated in Figure 6.7, and
explains why a cornerstone of treatment for angina is
reducing heart rate.
By reviewing the comments on cardiac blood ow in
Chapter 5 we can consider the consequences of changes
in preload and afterload, as explored in Box 6.2.
Understanding these relationships enables us to
recognize what contributes to angina; for example, we
can see that hypertension, or stress, with sympathetic
overactivity, will exacerbate the situation. Importantly it
also helps us to understand the rationale behind its drug
treatment.
6.4.2 Types of angina
e three types of angina can be directly related to the
processes responsible for the partial occlusion of
coronary arteries, which in turn lead to the episodic pain
Systole
Aortic pressure
Diastole
experienced by the suerer. ese processes are depicted
in Figure 6.8.
Stable angina is the most common form, and is also
referred to as typical angina. It is due to an atheroma
which reduces the maximal capacity of a coronary artery
by presenting an obstruction to the ow of blood. e
changes to the wall of the artery result in the vessel’s
being unable to dilate appropriately when required to do
so in order to meet an increased demand of the
myocardium for oxygen. ‘Stable’ does not mean that the
ischaemia/pain is always there, but that it does not occur
at random. Pain or discomfort is elicited by specic
precipitants, such as exertion or stress, and so the
condition might be better referred to as predictable
angina. Symptoms are nearly always relieved by rest. e
precipitating factors can be understood in terms of
upsetting the myocardial oxygen supply–demand
relationship discussed above.
Unstable angina presents as irregular accelerations of
symptoms, often with rapid progression. It is caused by
rupture of the surface of an atherosclerotic plaque, with
platelet plug formation (arterial thrombus; see Chapter 4)
which rapidly reduces blood ow. e platelet plug may
dissipate, restoring ow, only for the process to be
repeated, or for a more stable thrombus to form. Unstable
angina requires urgent treatment, partly because of the
discomfort caused, but mostly because complete
occlusion may occur, with progression to MI. e same
dire outcome can result from part or all of the thrombus
breaking away and blocking blood vessels further
downstream.
LV pressure
Figure 6.7 Why slowing the heart rate increases oxygen
supply to the heart.
During ventricular systole the rise in pressure within the ventricle
wall compresses the blood vessels within it, reducing blood flow.
This effect is greatest in the left ventricle (LV) and in the tissue
closest to the inside of the ventricle (the sub-endocardial layer).
Maximum blood flow to the muscle cells of the ventricle wall
occurs during diastole, when ventricular pressure is lowest.
Consequently slowing the heart rate, and so increasing the
duration of diastole, increases coronary blood flow and oxygen
supply to the working myocardium.
Window for maximum
blood ow to left
ventricle muscle cells
Variant angina (also called vasospastic angina or
Prinzmetal’s angina) occurs rarely, and results from a
transient reduction of blood ow caused by coronary
artery spasm. is may be associated with coronary
atherosclerosis and occur in the vicinity of plaques; it
may, however, occur independently of atherosclerotic
disease. It can cause intense pain, not precipitated by
exertion, and often occurs in the early hours of the
morning when the patient is resting.
6.4.3 Drug treatments and angina
Long-term preventative drug treatment of angina is
almost exclusively aimed at reducing the progression of
atherosclerosis, covered above. Here we are concerned
with drugs used to relieve acute anginal pain, or to avert
the onset of an angina attack in a patient with a history of
this condition.