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WORKBOOK 3
Atherosclerosis, lipid-lowering drugs,
and ischaemic heart disease
The patient: a simplified case history
As the vicar announces that Andreas and Monique are now husband and wife, their family and
friends clap spontaneously. Everyone is relieved because the couple’s wedding was previously
cancelled at the last minute after Andreas was rushed into hospital. (He was diagnosed with a
hypertensive crisis and admitted to hospital for several days while his blood pressure was
brought under control.)
Two hours later, everyone is gathered in the reception venue laughing at a joke the best man
has made. Suddenly Andreas’s dad, Brian, collapses to the floor clutching his chest.
Dr Carter Brown, who is at the wedding with Sunita (Monique’s best friend), is quick to take
control. First he instructs Eoin to ring for an ambulance and then sits Brian up against the wall,
gives him aspirin tablets, and helps him to use a glyceryl trinitrate (GTN) spray. Ten minutes
later, after using the spray for the second time, Brian’s pain subsides.
Brian is rushed to hospital and admitted to the coronary care unit (CCU).
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR BRIAN KAISER
Age: 65 years
Weight: 70 kg
PC: Chest pain and nausea at rest
This means the chest pain did not start as a result of exercise. Note this for later.
HPC: Sudden onset of chest pain during reception at son’s wedding. Pain started in his chest and
radiated to his left shoulder and arm.
PMH:
1) Stroke 8 years previously
2) Dyslipidaemia, diagnosed at the same time
3) Hypertension
Brian has had a previous stroke, following which he was diagnosed with hypertension and
dyslipidaemia (his lipoprotein levels are above the recommended values).
WORKBOOK 3 Atherosclerosis, lipid-lowering drugs, and ischaemic heart disease 133
SH: Retired and lives with wife. Smokes 20 cigarettes a day.
DH:
1) Asasantin Retard®
2) Fenofibrate
3) Felodipine
4) Bendroflumethiazide
Asasantin Retard® contains a combination of two antiplatelet drugs, dipyridamole and aspirin,
to help prevent a further stroke.
Fenofibrate is given to reduce Brain’s cholesterol level. Elevated cholesterol increases his risk of
having a heart attack.
Felodipine and bendroflumethiazide are given for his hypertension.
O/E:
1) Blood pressure = 179/95 mmHg (ideal <140/90 mmHg)
His blood pressure is elevated and needs to be reduced.
2) Pulse = 60/minute (normal)
Smoking, dyslipidaemia, his age, and his sex combine to increase his risk of angina or a heart
attack.
Biochemistry:
1) Electrolytes
• Sodium = 143 mmol/l (normal 135–145 mmol/l)
• Potassium = 4.1 mmol/l (normal 3.5–5.5 mmol/l)
These are both within the recommended range.
2) Others
• Total cholesterol = 9.2 (ideal <4 mmol/l)
• LDL-cholesterol = 8.25 (ideal <2 mmol/l)
• HDL-cholesterol = 2.0 (ideal > 0.84 mmol/l)
• Triglycerides = 1.09 (0.8–1.7 mmol/l)
• Troponin I = 0.05 (<0.1 mcg/l)
• Blood glucose level <7 mmol/l (normal)
Total cholesterol, LDL-cholesterol and triglyceride levels are all indicators of dyslipidaemia. Brian’s
total cholesterol and LDL-cholesterol levels are extremely high.
Troponin measurement is used, alongside electrocardiography (see below), to determine whether he
has suffered a heart attack. He has not.
Brian’s blood glucose level is normal, ruling out diabetes which is another risk factor for ischaemic
heart disease.
3) Electrocardiogram (ECG): normal
Electrocardiography measures the electrical activity within the heart; this can change after a heart
attack. Together with troponin levels it is used to diagnose a heart attack.
134 Chapter 6 Atherosclerosis and ischaemic heart disease
Diagnosis: Acute coronary syndrome (ACS); unstable angina
ACS is a collective term for a spectrum of conditions which arise from a sudden decrease in the flow
of blood through a coronary blood vessel. ACS encompasses unstable angina, Non-ST segment
Elevation Myocardial Infarction (NSTEMI), and ST-Elevation Myocardial Infarction (STEMI) (see later).
Plan:
Admit
Change fenofibrate to simvastatin
Commence isosorbide mononitrate, clopidogrel, ramipril, and atenolol
Commence subcutaneous enoxaparin (a low-molecular weight heparin; see Chapter 4, Section 4.2.1)
The doctor explains to Brian that he has suffered an attack of unstable angina. Brian’s symptoms of
severe left-sided chest pain, accompanied by nausea, are classic signs of angina.
Brian has heard of angina attacks but not of unstable angina. The doctor explains that the heart, in order
to function, requires a steady supply of oxygen carried in the blood. In unstable angina the flow of blood
can be interrupted in an unpredictable manner—he insists that Brian needs immediate hospital treatment.
EXPLORING BRIAN’S ANGINA AND ITS DRUG TREATMENT
1a) What is angina?
1b) List the three types of angina.
1c) What is the difference between stable and unstable angina in terms of:
i) The experience of the patient?
ii) Events inside the coronary vessels?
1d) Why is unstable angina considered so much more dangerous than stable angina?
The doctor explains that angina and heart attacks (myocardial infarction; MI) are all
presentations of what is generally called ischaemic heart disease.
He tells Brian that angina could eventually lead to a heart attack, with increased blockage of the
blood vessels supplying the heart.
Ischaemic heart disease is a condition in which blood flow through the coronary arteries to the
heart muscle cells is impeded. The underlying process usually involves atherosclerosis, but ischaemia
can also result from vascular spasm of coronary arteries, although this is rare. Ischaemic heart
disease is also referred to as coronary heart disease and coronary artery disease. The severity of
symptoms, and the degree of damage done to cardiac tissue, depends on:
• extentofischaemia
• rateofischaemia
• durationofischaemia.
WORKBOOK 3 Atherosclerosis, lipid-lowering drugs, and ischaemic heart disease 135
Brian’s wife wants to know how this unstable angina can be managed.
The doctor tells her that the key to management is prevention. Part of this involves reducing, or
avoiding, factors that contribute to ischaemic heart disease. These are called risk factors.
Brian’s blood tests showed that one of the risk factors in his case is dyslipidaemia.
Dyslipidaemia is the term for altered plasma concentrations of cholesterol and triglycerides. In
Brian’s case LDL-cholesterol and total cholesterol are very high.
2a) What are lipoproteins?
2b) Name the main types of lipoprotein.
2c) List the roles of the different lipoproteins in the transportation of cholesterol, giving the relative
proportion of cholesterol transported by each.
3) Name the two types of plasma lipoprotein which, when elevated, increase the risk of ischaemic heart
disease.
The doctor informs Brian that the fenofibrate which he had been taking to treat his
dyslipidaemia does not appear to have been effective.
4) What evidence is this conclusion based on? (Look back at Brian’s notes.)
Brian says that initially he tried to treat his dyslipidaemia through changes to his diet. This had
been difficult, and, although he had lost weight, his levels remained high and fenofibrate had
been recommended.
The doctor tells Brian that the change in diet, combined with drug treatment, has not been
sufficient to lower his lipid levels adequately so as to halt the progression of atherosclerosis in
the arteries of his heart.
5) What is atherosclerosis?
6) What are the seven main steps involved in atherogenesis (pathogenesis of atherosclerosis)?
7) Endothelial cells and LDL interact in atherogenesis. Explain.
8) Name the main classes of drugs used to manage dyslipidaemia. Which group does fenofibrate belong to?
9a) The mechanism of action of fibrates involves an effect on lipoprotein lipase. What is the effect?
9b) Explain how this is beneficial.
10) What is the most common side effect of fibrates?
The doctor explains to Brian that the fenofibrate is being replaced by simvastatin. Brian would
like to know why he cannot use both drugs together, so that his lipid levels will drop more quickly.
136 Chapter 6 Atherosclerosis and ischaemic heart disease
11) Why are both drugs not used together?
Clue: Do statins cause myositis?
12) What is the mechanism of action of statins? In your answer explain how statins affect the uptake
and release of different lipoproteins by the liver.
The pharmacist tells Brian that simvastatin has to be taken at night. She also advises him to
avoid grapefruit juice.
13a) Why should simvastatin be taken at night?
13b) Why should Brian avoid grapefruit juice?
Brian is very worried that he might forget to take his tablet at night; he prefers to take all his
tablets in one go, in the morning. He voices his concern to the pharmacist when she is
reviewing his notes. She is alarmed at how high his cholesterol levels are, and discusses this
with the doctor. Together they agree to change simvastatin to atorvastatin.
13c) Why was atorvastatin chosen over simvastatin?
Clue: Compare the duration of action of the two statins, and their effectiveness in lowering
LDL-cholesterol (see Section 6.3.2).
Andreas and Monique come to visit Brian. They ask him what the doctors have said. Brian has
been told to reduce his ‘risk factors’, to prevent a heart attack.
Andreas, who has recently suffered a hypertensive crisis, says he has been told to do exactly
the same.
14a) Explain why hypertension is a risk factor for the development of ischaemic heart disease.
14b) Explain why reducing hypertension in a patient with established ischaemic heart disease is likely to
reduce ischaemic events.
14c) Name another risk factor for ischaemic heart disease that Brian could reduce.
15) Altering the balance between oxygen supply and demand is very important in the treatment of
angina. List two ways of achieving this. Which drugs is Brian given to do this?
Clue: Think of one class of drug that could increase the size of blood vessels, and another which
affects cardiac work directly by decreasing heart rate and force of contraction.
The pharmacist tells Brian he should take his isosorbide mononitrate tablets twice a day, at
8am and 2pm i.e. at irregularintervals.Sheinsiststhatheshouldtaketheseconddose6–8
hours after the first, giving a large gap before the next dose. In this way, the concentration of
the drug in the body is low for 4–8 hours every day.
WORKBOOK 3 Atherosclerosis, lipid-lowering drugs, and ischaemic heart disease 137
16a) Explain the mechanism by which organic nitrates cause vasodilatation of Brian’s blood vessels.
(See Chapter 5, Box 5.2.)
16b) Why should nitrates be taken at irregular intervals?
16c) Name one side effect of nitrates that affects most patients.
The pharmacist advises Brian that if he gets a headache he should ask for paracetamol. She
explains that headache is a common side effect of nitrates, caused by increased blood flow to
the brain.
The following day, Brian complains of indigestion; the pharmacist explains that it is possibly
due to gastric irritation brought about by the combination of aspirin, dipyridamole, and
clopidogrel (see Chapter 4).
Note: Aspirin and dipyridamole were originally prescribed (as the combined Asasantin Retard®)
because of Brian’s earlier stroke, not because of his current problems.
17) Why might this combination of drugs have led to Brian’s indigestion?
On the pharmacist’s recommendation, the Asasantin Retard® is replaced with aspirin (75 mg),
andlansoprazoleisprescribedtoprotecthisstomach.(Lansoprazoleisaproton-pumpinhibitor
given to prevent stomach ulcers; see Chapter 12.) The pharmacist also tells him to take the
aspirin and clopidogrel after food.
Brian wants to know how clopidogrel works. The pharmacist explains that it prevents platelets
from sticking together and blocking the blood vessels in the heart.
18) Explain in more detail the mechanism of action of clopidogrel (see Chapter 4, Section 4.2.2).
When Andreas and Monique come in to see Brian again, they tell him that Sunita has just found
out that Dr Brown was two-timing her. Sunita is heartbroken. Is there now a chance for Eoin and
Sunita to get together?
Brian is informed that he will be kept in hospital for a few days.
PROGRESSION TO A HEART ATTACK (MI)
During the night Brian complains of severe chest pain and the doctors are called immediately.
Blood tests are repeated and an ECG is done.
138 Chapter 6 Atherosclerosis and ischaemic heart disease
1) Troponin I = 4.1 (<0.1 mcg/l)
Troponin I and T are intracellular proteins released from damaged heart muscle when ischaemia leads
to cell death (necrosis). The presence in the blood of either one therefore indicates that necrosis of
heart muscle has occurred during myocardial infarction.
2) Electrocardiogram: ST segment is not elevated; however, there is ST depression in two leads.
The abnormal ECG, together with elevated blood troponin level, is diagnostic of an MI; the ECG does
not show an elevated ST segment, and therefore the MI is designated as a non-ST-segment elevation
myocardial infarction (NSTEMI).
3) Blood pressure = 195/95 mmHg
Diagnosis: NSTEMI
Plan:
Change isosorbide mononitrate tablets to glyceryl trinitrate infusion
Commence tirofiban infusions for 72 hours minimum
The cardiologist explains to Brian that while he previously had unstable angina, during the night
he had a mild heart attack. Brian overhears the cardiologist telling the junior doctor that the
heart attack was probably caused by a ruptured plaque, which is a common consequence of
atherosclerosis. He also hears them discussing acute coronary syndrome (ACS).
Brian asks the doctor to help him understand whether his diagnosis is ACS or NSTEMI.
19) Explain what is meant by the term acute coronary syndrome. Which conditions does it encompass?
The cardiologist tells Brian that the unstable angina has progressed and led to a minor heart
attack. His treatment must now be aggressive in order to prevent a STEMI, which is a full-blown
heart attack.
The doctor explains that one of the infusions Brian is receiving, glyceryl trinitrate, will help
prevent angina by reducing the work his heart is doing.
20) Why is this reduction in cardiac workload helpful for patients recovering from an MI? Bring preload
and afterload into your answer when you explain the consequences of GTN infusion on cardiac work.
Once Brian is considered stable, his nitrate (GTN) infusion is discontinued and he returns to oral
nitrates in the form of the isosorbide mononitrate tablets that he was taking earlier.
The pharmacist explains that he is now receiving injections under the skin (subcutaneous) of
heparin (in this case a LMWH called enoxaparin, see Chapter 4) together with an infusion of a
second drug, tirofiban. These two drugs have anticoagulant and antiplatelet effects,
respectively, to protect against further clots forming and blocking his coronary arteries.
WORKBOOK 3 Atherosclerosis, lipid-lowering drugs, and ischaemic heart disease 139
21a) Explain exactly how tirofiban prevents platelet aggregation.
Clue: Cast your mind back to glycoprotein IIb/IIIa receptors (Chapter 4, Box 4.2).
21b) Set out how tirofiban and heparin help stabilize Brian, preventing further coronary artery occlusion.
The next day Brian is still complaining of chest pain, and is given nicorandil to help alleviate his
discomfort.
22a) To what class of drugs does nicorandil belong?
22b) What is the mechanism of action of nicorandil and how might this help Brian?
Andreas and Monique come to visit Brian. As they chat, Brian suddenly clutches his chest and
gasps for air. His ECG monitor starts beeping. Andreas calls the nurse. She runs to Brian and
presses a red button at the top of his bed.
An alarm goes off, the curtains are pulled round, and several doctors and nurses come running.
Andreas and Monique are told to wait outside.
Later, Andreas is told that Brian has suffered a major heart attack (a STEMI). The doctors
suspect a blockage in one of his main coronary arteries.
Andreas wants to know if Brian was ‘thrombolysed with streptokinase’ after his NSTEMI (see
Chapter 4). He argues that this should have been done when MI was first diagnosed. The
doctor defends his position, on the grounds that thrombolytics are not used in NSTEMI. He
adds that Brian’s very high blood pressure and his previous stroke both contraindicate
thrombolysis.
23a) What does ‘thrombolysed with streptokinase’ mean? (Thrombolysis is a synonym for fibrinolysis.)
What is the aim of giving a fibrinolytic drug to a patient who has had a myocardial infarction?
23b) What is the mechanism of action of fibrinolytics?
24a) If a patient has previously been given streptokinase, this drug cannot be used again. Why is this?
24b) What are the alternatives to thrombolysis for such a patient?
Andreas suggests angrily that the right decisions, which might have prevented Brian’s
progression to a STEMI, were not taken.
25) Do you think that Andreas’s attitude is justified, and that wrong decisions were taken which have led
to Brian’s situation worsening?
The doctors decide to proceed with immediate percutaneous coronary intervention since
thrombolytics are contraindicated.
140 Chapter 6 Atherosclerosis and ischaemic heart disease
Percutaneous coronary intervention (PCI) covers the procedures used to widen coronary arteries
that have been narrowed by atherosclerosis. These procedures involve balloon angioplasty usually
followed by stent insertion at the site where the artery narrows. PCI is a much less invasive
procedure than the alternative, bypass surgery. PCI can be performed to reduce or eliminate the
symptoms of ischaemic heart disease (e.g. angina) or to abort an acute myocardial infarction. It is
generally reserved for patients at high risk, or where pharmacological treatment is not tolerated or
is not adequately controlling angina symptoms.
DuringthePCI,thecardiologistrealizesthattwomoreofBrian’scoronaryarteriesareblocked
to varying degrees.
The team performs balloon angioplasty using a balloon fed via a catheter through his femoral
artery to the site of the blockage, where it is inflated to widen the narrowed (stenosed) artery. A
stent (a small tube of stainless steel mesh) is inserted at the site, via the catheter, and keeps the
artery open. The balloon is then deflated and withdrawn. Brian will have to take clopidogrel for
a year to prevent platelets from aggregating round the stents and forming clots. He must also
continue to take aspirin lifelong, because of its antiplatelet effects.
Brian is receiving the following drugs in addition to his other medication:
• oxygen(topreventhypoxaemia)
• morphine(forpainrelief;givenwithanantiemetic)
• atenolol,a-adrenoceptor antagonist (-blocker).
26) What is the effect of -blockers on cardiac work?
The doctor tells Brian that his felodipine tablets will be discontinued, but the dose of -blocker
will be increased. Brian is worried that his blood pressure will rise without the felodipine. The
doctor and pharmacist explain that the -blocker is an antihypertensive, and he is also taking
thediureticbendroumethiazide.Inaddition,heisnowtakingafurtherantihypertensivedrug,
ramipril, which is an ACE inhibitor (Chapter 5). Ramipril also helps to prevent heart failure
following a heart attack.
27) What is the mechanism of action of ACE inhibitors? How will this be of benefit in Brian’s case? (See
Section 5.2.1.)
An echocardiogram is ordered. It shows that Brian now has left ventricular dysfunction and
signs of heart failure. He is started on eplerenone, which clinical trials have shown could
improve outcomes for those with evidence of heart failure following a heart attack.
28) To what class of drug does eplerenone belong? (See Chapter 5, Section 5.2.1, and Chapter 7,
Section 7.5.1.)
WORKBOOK 3 Atherosclerosis, lipid-lowering drugs, and ischaemic heart disease 141
After 2 weeks in hospital, Brian is discharged on the following tablets:
• aspirin
• clopidogrel
• isosorbidemononitrate
• nicorandil
• atenolol
• eplerenone
• ramipril
• atorvastatin
• lansoprazole.
A letter is sent to Brian’s GP advising that:
• hislipoproteinlevelsshouldbemonitored
• thedosesofACEinhibitorand-blocker should be increased as tolerated
• clopidogrelshouldbecontinuedfor1year
• aspirinshouldbecontinuedforlife.
When Brian gets home, he is surprised to see Sunita and Eoin, who seem very happy and
excited, if a bit nervous. They have some news for him—they have decided to get married in a
month’s time. They would like to have the wedding in Singapore where Eoin’s next competition
isscheduledin3weeks’time.