Page 1

TARGET HEART DISEASE


CONTENTS

The costs and benefits of medicines for heart disease

INTRODUCTION

1

THE HEART IN HEALTH AND DISEASE

2

QUESTIONS AND ANSWERS ABOUT HEART DISEASE

6

DIAGNOSIS AND INVESTIGATION OF HEART DISEASE

14

HEART DISEASE AND THE PHARMACEUTICAL INDUSTRY

16

CONCLUSIONS

35

SUMMARY TABLE

36

Acknowledgements

The ABPI wishes to thank the companies who provided help and the information necessary in the preparation of this booklet and also the British Cardiac Patients Association for their invaluable support and comments. We are also indebted to the Science Photo Library for the use of images, which are gratefully acknowledged.

December 2004

Researched and written by Dr Mike Hall Target Series Editor: Bill Kirkness

Heart disease is the biggest killer of people under 75 and costs the NHS over £2 billion a year. Nearly 20 per cent of all deaths in the UK are from diseases of the heart, while cancer is responsible for around 13 per cent. In percentage terms, heart and circulatory disorders account for 11 per cent of gross NHS expenditure, compared with eight per cent and five per cent respectively for mental/nervous and respiratory disorders and four per cent each for cancer, digestive and genito-urinary disorders. The Government’s National Institute for Clinical Excellence, which issues guidance on a range of conditions and their treatment, has published extensive information on the cost-effectiveness of medicines in the treatment of heart disease. It measures medicines according to the cost per a year of life gained through its use and has concluded that, for conditions related to myocardial infarction, “all available treatments are estimated to be cost-effective”. Similarly, for chronic heart failure, ACE inhibitors and beta-blockers were also found to be costeffective. An important element in considering all treatment with medicines is not just the cost, but the quality of life that they provide – people live longer, healthier lives and can enjoy work, leisure and their daily lives better if their heart condition is under control. Most heart medicines act in the long term, (especially the statins, which aim to reduce the build up of cholesterol levels in the body) and the results of medication with lipidlowering medicines may not be seen for many years. Studies suggest that treatment with statins “compares favourably with several other interventions currently provided by the NHS”.

The Association of the British Pharmaceutical Industry 12 Whitehall London SW1A 2DY Telephone: 020 7930 3477 Fax: 020 7747 1411 E-mail: abpi@abpi.org.uk Website: www.abpi.org.uk


INTRODUCTION The heart has long been associated with the very nature of humanity. As long ago as the fourth century BC, Aristotle considered it to be the seat of the soul, the centre of nutrition and the vital source of heat. The very word ‘heart’ is still deeply embedded in our language in phrases such as ‘heart-felt sympathy’, ‘heart-to-heart talk’, or ‘the heart and soul of the party’, no doubt reflecting its central location in the body and its regular beat. It is also associated with many emotional sensations, so heart disorders hit at the very core of a person’s fabric and psyche.

Medicines for the heart have a long history. Descriptions of heart failure can be found in ancient Egyptian, Greek and Indian documents, and we know that the Romans used foxglove as a medicine long before its ‘discovery’ by William Withering in 1785. A plant in the same family, figwort, was used as a diuretic to eliminate excess water, while lily-of-the-valley, hawthorn berries, valerian and passion flower have been used variously for heart failure, irregular heart beat and angina for centuries.

Our ancestors had little idea how herbal medicines worked. There was only the vaguest understanding of bodily functions and many remedies must have emerged purely by chance. But as understanding increased, ignorance slowly gave way to enlightenment. In the early 17th century William Harvey discovered the circulation of the blood, and over the next 300 years many aspects of the heart’s structure and functions were clarified. These included its pumping action, the volume of blood flow, and the discovery of the heart’s internal ‘nervous’ system and pacemaker. Such studies led to the first electrocardiograph around 1880, and culminated in the development of heart bypass surgery in the 1950s and the first heart transplant by Christiaan Barnard in 1967.

After aspirin, perhaps one of the best known of all heart medicines is nitroglycerin (the ‘tablet-underthe-tongue’). Introduced 125 years ago, it still plays a key role in the treatment of angina, helping many people enjoy a better quality of life. Since then, many new types of medicine have been discovered, such as diuretics for controlling fluid excretion via the kidneys, beta-blockers, ACE inhibitors and angiotensin II antagonists for high blood pressure and heart failure, thiazides for heart failure, statins for high cholesterol, and calcium antagonists for arrhythmia, high blood pressure and angina. These have been developed largely through the efforts of the pharmaceutical industry, in partnership with medical faculties throughout the world. Despite the huge number of medicines already available and dozens in development, there remains much to do.

In this short booklet, the features and treatment of five common heart conditions will be considered. These are atherosclerosis, angina, myocardial infarction (heart attack), heart failure and arrhythmia. Of particular importance are new medicines in the pipeline which may work in people where others have not been effective. However, it should be stressed that this is not a treatment guide, but a platform for understanding and information for those with heart disease and their families and carers.

1


THE HEART IN HEALTH AND DISEASE External features of the heart viewed from the front, showing the left and right coronary arteries and other major structures RA, LA = right and left atrium; RV, LV = right and left ventricle; SVC & IVC = superior and inferior vena cava

Chambers of the heart showing major arteries and veins, valves and the direction of blood flow. Deoxygenated blood is shown in purple and oxygenated blood in red. The two do not mix, showing that the heart is two separate pumps operating together. ASV, PSV= Aortic and pulmonary semilunar valves

2

The structure of the healthy heart The adult heart is about the size of a clenched fist and weighs between 250 and 390 grams in men, and 200 to 275 grams in women. It is located in the centre of the chest cavity and is tipped diagonally, with about two-thirds of its bulk left of the body’s midline and the apex pointing left. The heart is suspended in the chest cavity in a multilayered membrane called the pericardium which helps keep it in place. Viewed as if through the opened chest, it is possible to distinguish the large muscular masses of the left and right ventricles (the main pumping chambers) and above them the smaller and thinner walled left and right atria. On the surface of these chambers are grooves along which several of the major arteries run, including the coronary arteries. Approaching the heart are many large blood vessels, some returning blood from the body to the heart, and others carrying blood away to the lungs and other parts of the body. If we look inside the heart, it is immediately clear that it is a hollow structure with a vertical wall of muscle (the septum) dividing it into its right and left sides. Blood within these two halves does not mix. Rather, they operate as a double pump, that on the right handling deoxygenated blood and that on the left the blood which has been oxygenated in the lungs. The deoxygenated blood flowing back towards the heart through the superior and inferior vena cava enters the right atrium and then passes through the tricuspid valve into the right ventricle. Similarly, oxygenated blood from the lungs enters the left atrium and passes to the left ventricle through the mitral or bicuspid valve. A second pair of valves, the semilunar valves, guard the exits of the ventricles to the aorta and the pulmonary arteries. The tricuspid and mitral valves close when the heart contracts to prevent the back-flow of blood while the semilunar valves open, and vice versa. The valves themselves are not free flaps, but are tethered to the ventricular or arterial walls by fibrous strands.


Blood is supplied to the heart itself (coronary circulation) along the left and right coronary arteries which are the first branches off the aorta. Most blood goes to the left side, where the greatest amount of work is done. It should be noted that there is some collateral circulation – some blood passing along the left coronary artery goes to the right heart and vice versa. A blockage does not necessarily mean a total loss of blood supply – that will depend on the exact location of the blockage.

Specially prepared human heart showing the coronary artery and cardiac vein and the intricate network of blood vessels feeding the ventricles

The heart beat is regulated throughout life, whether you are awake or asleep, and in response to physical exercise or emotional experiences, by an internal system of electrical conducting fibres. These are modified heart muscle cells that function like the nerves in the rest of the body and are quite separate from the brain and central nervous system.

Function and control mechanisms of the healthy heart The heart begins to function well before any other organ in the body and a baby’s first heart beats begin in the fourth week of embryonic development. It then continues non-stop throughout life, completing about 2.5 billion beats in a 70 year life span. The heart beats at about 72 times per minute at rest (once every 0.8 seconds). During one minute, the heart pumps five to six litres of blood, the equivalent of 7,200 litres a day. All this is pumped either from the right ventricle to the lungs, where carbon dioxide waste is removed from the red pigment, haemoglobin, and replaced by oxygen, or from the left ventricle to the rest of the body to

distribute necessary chemicals such as nutrients, hormones and oxygen. The amount of blood pumped (cardiac output) varies considerably, depending on the level of exercise. It can triple if exercise is strenuous (Table 1) and its distribution to the various organs changes dramatically, with the greater amount going to the skeletal muscles. Blood is not able to penetrate from the heart chambers directly into the heart tissue. Instead, it has to be carried to the hard-working heart muscles through the heart’s own blood vessels. Every day about 380 litres travel to the heart’s own tissues. Because there is almost no energy stored in the heart, the blood supply has to be continuous to maintain healthy function.

ORGAN

AT REST (%)

DURING EXCERCISE (%)

Abdominal organs

1.4 (24)

0.6 (3.5)

Skeletal muscles

1.2 (20)

12.5 (72)

Kidneys

1.1 (20)

0.6 (3.5)

Brain

0.75 (13)

0.75 (4)

Skin

0.5 (9)

1.9 (11)

Heart

0.25 (4)

0.75 (4)

All other

0.6 (10)

0.4 (2)

TOTAL Litres/min (%)

5.9 (100)

17.5 (100)

Table1 Distribution and volume of blood flow (cardiac output) during rest and during strenuous activity, in litres/minute and as a percentage

3


Electrical conducting fibres (in green) that carry impulses from the sinoatrial node (SAN) and the atrioventricular node (AVN) to heart muscle to regulate heart beat. SVC & IVC = Superior & inferior vena cava; RA, LA, RV, LV = right and left atria and ventricles

branch bundles and Purkinje fibres, initiating a strong and co-ordinated heart beat.

SVC

Sinoatrial node [SAN]

Mitral valve

Atrioventricular node [AVN]

RA

LA

Interventricular septum

RV

LV

The initiation of each beat is brought about by the rapid flux of charged particles (ions) through cell membranes, the most notable of which is calcium (Ca2+). However, sodium (Na+), potassium (K+) and hydrogen (H+) ions are also major players in both heart beat and vascular ‘tone’ (the constriction and dilation of blood vessels), though exactly which does what and where varies considerably with the tissue. Details of how these ion fluxes are regulated will not be described in any detail, though they do provide important targets for the design of new cardiovascular medicines.

IVC

Right branch bundle

Muscular septum between ventricles Left branch bundle

The electrical stimulation that starts a heart beat and controls the rhythm begins in a specialised mass of modified muscle tissue in the upper wall of the right atrium in what is called the sinoatrial node – or SAN. The SAN is the heart’s natural pacemaker and normally ‘fires’ at a rate of 70 to 80 times a minute. The signals from the SAN spread out across the right atrium rather like the ripples on a pond until they encounter another node of tissue called the atrioventricular node or AVN. This takes a few hundredths of a second and causes the contraction of the atria. The AVN acts as a delaying point for the electrical wave, lasting about 1/10th of a second before allowing it to pass down though the septum separating the left and right heart. It then spreads out into the whole of the ventricular muscle through the left and right

Scanning electron micrograph of the conducting Purkinje fibres (greenish yellow) within the cardiac muscle (red)

Besides ion movements, heart rate can be influenced by the brain and some hormones. For example, nerves of the autonomic nervous system (those that operate without conscious control) can interact with the SAN to raise or lower heart rate, depending on the circumstances. Other factors such as hormones, blood temperature and acidity, anger, pain, fever and grief can also change the heart rate. By placing electrodes on the chest and limbs, doctors can detect the various features of the wave as it spreads across the heart. These can be displayed on a monitor or printed on paper as an electrocardiogram (ECG). The ECG is very helpful in diagnosing a variety of heart complaints.

4


The diagram shows a normal ECG

Atrial depolarisation

Ventricular depolarisation

Ventricular repolarisation

For example, a heightened P wave indicates an enlarged atrium, a deeper than normal Q wave may indicate a heart attack (myocardial infarction, MI) and a heightened R wave usually indicates a thickened ventricular wall. An ST segment raised above the horizontal often indicates acute MI, while if it is below the horizontal it is often indicative of high blood potassium levels.

R

1.0

Voltage (mV)

recording. Each spike and trough on the graph corresponds to a specific event in the cycle of a heart beat. By examining the frequency and duration of ECG waves, much information can be gathered about heart function and malfunction.

S-T segment

P-R segment

0.5

T

P 0 Q S

–0.5

QRS complex 0

0.2

0.4

Time (sec)

Simplified normal electrocardiogram (ECG) and its use in diagnosis

0.6

0.8

Any deviation from the normal rate or sequence of the ECG is called a cardiac arrhythmia. If the SA node is damaged, the heart rate may slow to 40-50 beats per minute and if both SAN and AVN are damaged, it may fall to 20-40 beats per minute and require an artificial pacemaker.

When things go wrong It will be obvious from the complex structure and regulation of the heart that many problems can arise. These may affect any of the heart’s components, such as the valves, muscles, blood vessels, the blood itself or the conducting fibres that control heart rhythm and rate. In this booklet, only five types of heart disorder will be considered, namely: • atherosclerosis – the build up of fatty material and cellular debris (atheroma) inside blood vessels that can restrict blood flow • angina – sharp chest pains experienced when exercising due to inadequate blood supply to the heart muscles, often as a result of atherosclerosis • myocardial infarction – blockage of the arteries that feed the heart, causing a heart attack

• heart failure – a weakening of the heart’s pumping capacity to such an extent that it no longer maintains blood output adequate for the body’s requirements • arrhythmia – an irregular heart beat which may affect both ventricles and atria. There are many other disorders that can affect the heart and associated structures. These include infections of the muscles (e.g. myocarditis), valves or blood vessels, physical damage to the valves, immune disorders that result in destruction of heart tissue, congenital defects (e.g. ‘hole in the heart’), and also conditions that affect the pericardium, the sac in which the heart is enclosed. Most of these are beyond the scope of this book and will only be mentioned briefly.

5


HEART DISEASE Some Questions and Answers Which heart conditions and treatments are covered in this booklet? In a short booklet like this, it is not possible to discuss all possible heart conditions. Instead it has focused on the commonest disorders mentioned above. The causes and treatment of high blood pressure (hypertension) are not covered, but are mentioned in several places, as it is an important risk factor in heart disease generally. The treatments discussed are mainly medicines, but the booklet would have been incomplete without some reference to the surgery that plays such a vital role in the treatment of many cardiac conditions. We have now reached a generation where bypass surgery and the use of stents (devices inserted into blood vessels to force open their walls) are commonplace, and heart transplants no longer attract headlines.

What is atherosclerosis? Atherosclerosis is the build up of plaque (atheroma) inside arteries that eventually begins to restrict blood flow and narrow the blood vessel. Plaques can be detected even in young people as ‘fatty streaks’ inside blood vessels and often go on to form quite complex structures in later life. They tend to occur more frequently in some arteries than others, and are especially common in parts of the aorta, coronary, carotid (head and face) and renal (kidney) arteries. Section of the coronary artery showing an unstable plaque halfblocking the vessel with a developing blood clot attached to it

6

As the plaque grows, it may develop a fatty core containing cholesterol and become covered with a fibrous cap. If this cap is thick, the plaque may be ‘stable’, but if it is thin, the surface may rupture and trigger the formation of blood clots (called an unstable plaque). Eventually, this build up becomes so large that it narrows the arteries, which in turn restricts blood flow. When this occurs in the heart, it is often referred to as ischaemia, and the heart is said to have ischaemic heart disease.

What is cholesterol and what does it do? Cholesterol is a key component of cell membranes. It is also the starting material from which steroid hormones are made by the adrenal gland. Problems arise when there is an excess of cholesterol in the blood. Chemically, cholesterol has the properties of a lipid (fat) and will not dissolve in water. Hence it has to be transported around the body attached to components of particles known as lipoproteins. There are several forms of cholesterol-carrying lipoproteins known as HDL, LDL, and VLDL (High Density Lipoprotein, Low Density Lipoprotein and Very Low Density Lipoprotein). The main culprits in heart disease are LDL and VLDL, often called ‘bad’ cholesterol, in contrast to the ‘good’ cholesterol known as HDLs. Raised levels of LDL and VLDL correlate with an increased risk of atherosclerosis and heart disease and are referred to as hypercholesterolaemia or hyperlipidaemia (‘hyper’ meaning high).

What are the signs and symptoms of atherosclerosis? In its early stages, atherosclerosis is a ‘silent’ condition (i.e. symptomless) and is now regarded as a form of chronic inflammation of the blood vessel lining. When the condition becomes sufficiently marked to restrict blood flow, symptoms begin to develop. These range from mild angina to myocardial infarction (heart attack). Each of these is described below.


What is angina?

Section of a heart showing an area of myocardial infarction (darker area on the lower left). The wall of the left ventricle is also much thickened (ventricular hypertrophy or enlargement) compared to that on the right

Angina is the name given to cramping chest pains, possibly with shortage of breath, associated with exercise. It is caused when cardiac muscles become starved of nutrients (especially oxygen) due to a narrowing of the arteries caused by atheroma. Because the heart demands more oxygen with higher levels of activity, angina pain often abates if a person stops exercising and rests. If angina attacks are increasing in frequency or duration, or are becoming evident even with minimal exercise, the condition is called unstable angina. This is more serious than stable angina, as it often progresses to myocardial infarction.

The abnormal ECG rhythm of a heart during a severe heart attack. This should be compared with the normal trace shown – on page 5

What are the symptoms of angina? Many people with restricted blood flow to the heart do not show any symptoms. Others may show good exercise tolerance without chest pain one day, but experience pain after minimal effort on another. Angina usually responds to nitroglycerin under the tongue, while a heart attack does not. In most people who require further clinical investigation, there will be a worsening of the pain in one of three ways. Firstly, there may be a sudden increase in the frequency, duration, or severity of the pain felt. Secondly, angina may be felt at rest. Thirdly, without previous symptoms of heart disease, there may be a sudden onset of severe pain.

What is a myocardial infarction? Myocardial infarction occurs when blood flow through the coronary artery is severely restricted or blocked. Over 90 per cent of these incidents are the result of the breaking up of an atherosclerotic plaque and the subsequent formation of a blood clot (thrombus).The formation of the blood clot converts an artery already narrowed by plaque into one with a severe or complete blockage in a relatively short time. If the blood flow is not restored quickly, the heart muscle is starved of vital oxygen and begins to die, with possible lifethreatening consequences. A heart attack may evolve through different stages over time. Initially, the lack of oxygen (ischaemia) will cause a loss of the ability of the heart muscles to contract normally. If this persists, the tissue begins to die (necrosis), and the heart rhythm shown on an ECG becomes very weak and

abnormal. The area of necrosis gradually enlarges, and around it develops an area of damaged muscle that (given treatment) can recover. Between 18 and 24 hours after the attack, white blood cells begin to accumulate at the site of damage and by the fourth day, scar tissue starts to form and new capillaries grow. During the whole of the first two weeks, the outer sheath of the heart (the myocardium) is very soft and weak, with the risk of rupture. A rupture almost always results in sudden death and accounts for 10 per cent of deaths from heart attack. However, after this time, the remaining heart muscle begins to compensate for the damage, and the heart recovers.

What are the symptoms of MI? Several symptoms can be used to distinguish a heart attack from an angina attack. Firstly, the

7


pain is likely to be more severe (often referred to as a ‘crushing’ pain), to last longer and to radiate further than that of angina into the arms, shoulder or jaw. It does not decrease with rest or respond to nitroglycerin. Heart attack patients also often sweat and have clammy skin, may feel sick and weak, have a mild fever and are very anxious.

‘flutter’. If that occurs in the atrium, it is called atrial fibrillation – the commonest rhythm disorder, affecting nearly one in 10 of the very elderly (80 to 89 year olds. However, it is important to realise that there are many different kinds of arrhythmia (e.g. palpitations or ‘missed beat’) that are not directly related to heart failure.

What is heart failure?

Is a ‘missed beat’ a kind of arrhythmia?

Heart attack, unstable angina and a history of high blood pressure can all contribute to a weakening of the heart and eventual heart failure. This occurs either when the heart can no longer pump blood out of the ventricles as quickly as it enters the atria, or when the ventricles do not pump equal amounts of blood. Over a period of time, the heart may attempt to compensate by enlarging. However, an enlarged heart is not a welcome sign, but more an indicator of developing heart failure. As heart failure progresses, the circulation becomes unbalanced and fluids may start to build up in the lungs or abdomen. In addition, the metabolic needs of the body are not adequately met and systems failure may start to appear in other organs such as the kidneys. However, many people with well-controlled heart failure live fairly active lives.

What are the symptoms of heart failure? This is a complex condition that may affect either the left and/or the right side of the heart. However, common symptoms are a shortage of breath on exercising, shortage of breath aggravated by lying flat, weakness and/or fatigue, possible mental dulling due to poor brain circulation, and fluid accumulation in the legs. In right-sided failure, there may also be abdominal discomfort, and decreased appetite due to liver enlargement or fluid accumulation in the gut.

What is arrhythmia? Arrhythmia (a change in the strength or pattern of the heart’s rhythm) often accompanies heart failure or MI. This usually indicates that damage may have occurred to the pacemakers or conducting fibres that spread the electrical signals across the heart to trigger and regulate heart beat. The heart rate may also be very high or very low if the pacemakers are damaged. An extremely high heart rate may assume the appearance of a

8

Yes – but many people experience missed beats (or even several at a time), sometimes followed by a flurry of rapid shorter beats – often called ‘palpitations’. This is especially noticeable at rest, for example when in bed, and can be quite alarming. Missed beats are known as ectopic beats. They do not indicate heart disease in the great majority of cases and seem to be caused by slight abnormalities of electrical firing in the natural pacemaker. They can be caused by ischaemia, lack of oxygen while asleep due to nasal restriction, asthma, ion disturbances or to reactions to certain medicines. In a few people, the beats may stop for a sufficient length of time to cause a fall in blood pressure. If they are persistent, such symptoms may require the fitting of an artificial pacemaker, which generally cures the problem.

How common are these different forms of heart disease? In the UK, heart disease is the biggest cause of premature death, more than cancers of all kinds. In the USA, it has been the biggest killer in every year except one since 1900. Unfortunately, trends in heart disease continue to rise due to the aging population and changes in lifestyle. Heart failure and angina are also responsible for a greater reduction in the quality of life of patients than most other diseases. For the UK, the total figure of those with stable angina is around 2 million – one person in 30. It is thought that the condition is under-diagnosed and the true figure may be 20 per cent higher than this. Stable angina has a death rate of between two and four per cent a year if only one coronary artery is affected, but is higher if other arteries are also diseased. Unstable angina is a much more serious condition and based on data from the USA, about four per cent who enter hospital with this condition die within 30 days.


Are there relationships between atherosclerosis, angina, MI and arrhythmia?

Number of people in different age groups with coronary heart disease in the UK in the year 2002 and projections to 2027

4 3.5 3 2.5 2 1.5 1

16-24

25-34

35-44

45-54

55-64

65-74

2027

2025

2020

2015

0

2010

0.5 2005

Number of people with CHD (m)

Heart failure is estimated to account for five per cent of admissions to hospital wards, with over 100,000 admissions each year in the UK. Between three and 20 people per 1,000 of the population overall have heart failure but this rises rapidly to exceed one in 10 in the over 65s. The outlook for people who develop clinical signs of heart failure is still not very good. About half of these patients remain alive after five years, but of people with severe symptoms, only about 40 per cent survive for one year or more. Despite this unsatisfactory picture, modern therapies can now significantly prolong and improve the life of people with heart failure.

75+

Impact on the quality of life of angina, heart failure and some chronic illnesses

Better than normal QoL.

% change in quality of life

0

Yes. In many respects there is a gradual transition from plaque formation to heart attack (caused by the complete blockage of coronary arteries) and angina (the restriction of blood flow due to partial blockage) and finally to heart failure. These relationships are shown below.

-10 -20 -30 -40

Diabetes

-50 -60 -70 -80

Arthritis

Chronic lung disease

Angina Heart failure

-90 Worse than normal QoL.

Enlargement of the heart

High blood pressure (hypertension) Cigarette smoking

Diabetes

Raised pulse rate

Damage to lining of blood vessels Plaques form within arteries (Atherosclerosis)

Plaques break up

Inadequate oxygen supply Blockage of arteries (Thrombosis)

Angina or heart attack

Some risk factors in the development of heart disease [Adapted from The Cardiovascular System at a Glance, by Aaronson, Ward & Weiner, Second Edition, Blackwell Publishing, 2004]

Heart failure

Abnormal fat balance in blood Diabetes

9


What risk factors contribute to this chain of events? High blood pressure is a risk factor for most of these conditions. It is an especially sinister condition, because people with high blood pressure can feel entirely well: feeling healthy is not the same thing as being healthy. For that reason, most doctors take blood pressure measurements as part of routine health screening. Many effective treatments for high blood pressure are now available, but if untreated for a prolonged period, it can result in enlargement of the heart as it seeks to compensate for inadequate blood output. It is also a major contributing factor to the development of plaque. The situation is worsened if the person suffers from diabetes. This can cause damage to the inner lining of the blood vessels, encouraging new

If the blockage affects a relatively small branch of the coronary artery, the heart attack may be mild, but if it blocks a main artery, extensive damage and death may follow. If the blockage results in damage to the heart’s natural pacemaker or conducting fibres, the heart may beat very slowly or an arrhythmia may develop.

How is high blood pressure defined? Blood pressure is the force exerted by the blood on the inside of the arterial wall. It reaches a maximum when the ventricles contract (systole) and a minimum between the heart’s beats (diastole). Most text books refer to a ‘normal’ blood pressure of 120:80, but in reality, these values rise steadily throughout life. By the age of 60 to 70, the ‘normal’ pressures are more likely to be in the region of 145:90. It is important to bear this in mind when given values by a doctor. High blood pressure (hypertension) is described by the National Institute for Clinical Excellence as “persistent raised blood pressure above 140:90”.

170 160 150 140

Blood pressure

Changes in normal blood pressure with age in men (red) and women (green). Upper two lines are the systole and the lower the diastole

plaques to form and ultimately to break up. Plaque formation may be more rapid and extensive if there is an imbalance in the circulating blood fats and cholesterol. It is also enhanced by smoking, lack of exercise and excessive alcohol consumption. Together these factors can raise the pulse rate above normal and precipitate cardiac ischaemia, angina or heart attack.

130 120 110 100 90 80 70 20

Heart disease in men compared to women in different age groups

30

40 50 60 Age group

70

70+

In general, men are much more likely to suffer from heart disease than women, irrespective of age. Also, there are some racial differences, and black men of any given age group are more likely to have high blood pressure than non-black people of the same age group. There is also an increased risk in people who are the least educated and in the poorest groups in society. These susceptibilities partly reflect genetic differences within different racial groups, but also lifestyle choices made by men and women.

Prevalence: rate per 1000 250 200 150 100 50 0

0-34

35-44

45-54 55-54 65-74

Men

10

Who is most susceptible to the various heart diseases?

Women

75-84

85+

Death rates from heart disease vary in different parts of the British Isles, with the highest rates in Scotland. Only Slovakia fares worse than Scotland in this area, while all regions in Britain are worse than most other European nations –


Mortality rates from coronary heart disease per 100,000 of the population in men and women under the age of 75. Blue = men, red = women

200 180 160 140 120 100 80 60 40 20 0 Sc

lr

Fi

NI

E&W

Ge

especially so compared to Spain, Italy and France, where the rates are less than 50 per cent of those in the UK.

Are any heart diseases inherited? Many forms of heart disease are a consequence of an unhealthy lifestyle (lack of exercise, alcohol, smoking and diet) and a great deal can be done to avoid them. However, there are certain conditions to which genes contribute. Congenital heart disease affects about eight in every 1,000 live births. Some of these are attributable to single gene defects, but others may be due to maternal sickness, ingestion of toxic substances during pregnancy and to environmental factors. Many such defects are not discovered until months later or even until adulthood. People with such defects require special counselling with regard to exercise, pregnancy, risk of infection, insurance and employment. Heart disease in male family members under the age of 55 and women under 65 also implies an increased risk and this is almost certainly a reflection of inheritance. A specific form of genetic heart disease is known as familial hypercholesterolaemia. Here, individuals have a mutation that causes a defect in the receptor that removes low-density lipoproteins (LDL) from the blood. Consequently, they develop high LDL levels and develop premature atherosclerosis.

Sw

Gr

Ne

Be

Sp

It

Fr

Sc = Scotland; Ir = Irish Republic; Fi = Finland; NI = Northern Ireland; E&W = England & Wales; Ge = Germany; Sw = Sweden; Gr = Greece; Ne = Netherlands; Be = Belgium; Sp = Spain; It = Italy; Fr = France

Inheritance also plays an important part in high blood pressure. Of people with this condition, 95 per cent have what is known as essential hypertension – high blood pressure with no known cause. The remaining five per cent have other conditions that cause their high blood pressure. However, at present, no definite genetic markers have been identified. The genetic link is apparent because there is a much higher rate of raised blood pressure in close relatives than in the general population.

What types of medicine are used in heart disease? There are a very large number of medicines available for different kinds of heart disorder and the selection of which ones to use, or which combination, will depend on an individual’s circumstances. However, heart medicines mostly fall into several groups, with similarities as to how they act. The commonest groups are: • diuretics of several chemical classes that increase the elimination of water through the kidneys • beta-blockers – also of several different types – that block a specific kind of receptor called a beta receptor • ACE inhibitors that prevent the formation of angiotensin II that can cause raised blood pressure

11


• Angiotensin II receptor antagonists for heart failure • medicines that modulate calcium and potassium movement into and out of cells • anti-platelet and anti-clotting agents of several different kinds that reduce the risk of blood clot formation in the heart, or dissolve existing clots • medicines used when there are excessive fats (hyperlipidaemia) or cholesterol (hypercholesterolaemia) in the circulation • anti-arrhythmics – medicines used to control irregular heart beat. These different kinds of medicine will be further discussed in a later section and are listed in the tables.

What role does surgery have in treating heart disease? The period from 1950 witnessed a dramatic improvement in surgery to treat heart conditions Bypass surgery. The image is a 3D coloured electron beam tomography scan that provides a clearer image than a conventional CT scan. The transplanted artery can be seen running across the surface of the heart from top left to bottom right

Colour enhanced Xray showing an artificial pacemaker in position under the skin and the lead running into the heart

12

and, though beyond the scope of this booklet, some mention of the main forms of surgery is necessary for the sake of completeness. Generally, heart surgery falls into one of several categories. Quite a number of less critical heart problems can now be treated surgically via a tube called a catheter, thus avoiding the need for major surgery. These include certain forms of less extensive damage to heart valves, or procedures to remedy abnormal heart rhythm. Open chest surgery is performed for bypass operations and for valve replacement with either an artificial valve or a tissue valve. If clinical investigation shows that the coronary artery is severely restricted, then there will be considerable risk of a heart attack. In this case, a section of blood vessel is grafted onto the outside of the heart to bypass the partly-blocked area. It will be connected to the coronary artery above the site of blockage and rejoined below it, bypassing the damaged area. The transplanted blood vessels may be sections of vein removed from the leg, but increasingly, a section of artery is used instead, as this is much more resistant to the build up of new plaque. Fifty per cent of veins will develop new plaque by 10 years, compared to just 10 per cent of arterial grafts. The ultimate surgical technique used for heart disease is heart or heart/lung transplantation, pioneered by Dr Christiaan Barnard and first carried out in 1967. This ideally requires matched tissues, or if that is not possible, the use of powerful immunosuppressive drugs to prevent rejection. In 2003 there were 149 heart transplants and 15 heart-lung transplants in the UK, with a 5-year survival of about 72 per cent and 50 per cent respectively. Though they are a major surgical procedure, these operations are lifesaving for many of the people involved. Increasingly, common surgical techniques involve the fitting of a pacemaker, the use of inflatable balloon devices to force open blocked arteries (angioplasty), and the use of stents, rather than open-heart surgery. Pacemakers are devices that replace or support the function of the natural pacemaker and help regulate or normalise heart rhythm, especially low heart rate (bradycardia). External temporary pacemakers may be used during emergencies, but the type most people are familiar with are the permanent pacemakers. These are inserted under the skin of the chest and are connected by fine wires to the right atrium or right ventricle. The


pulse generator is only the size of a small matchbox, but is essentially a small computer. Today’s versions can sense the state of electrical activity in the heart and send a pulse of electricity to the heart as required. The battery life today is between 10 and 12 years, and the pacemaker can be reprogrammed externally, using radio signals through the skin. Angioplasty requires the insertion into an artery of a long flexible tube (a catheter) tipped with an inflatable balloon. This is then threaded into the heart and the balloon positioned in the region partially blocked by plaque. The balloon is then inflated under high pressure, which has the effect of forcing apart the atherosclerotic walls and improving blood flow. The catheter is then withdrawn. This operation is usually very successful and has low risk, but about one-third of patients develop symptoms again within six to nine months. Fortunately, the development of stents has advanced rapidly in the last decade and this greatly improves the success rate of angioplasty. A stent is a stainless steel fine-mesh support device. It is threaded into the heart as described above, but when the balloon is inflated, the steel mesh is expanded and left in place when the catheter is withdrawn as a form of internal support. Stents greatly reduce the rate of recurrence of arterial narrowing. To prevent the build up of blood clots on the stainless steel mesh itself, patients will normally take anti-platelet medicines for at least the first month.

Coloured X-ray angiogram showing a balloon catheter being threaded into the heart from the top left. The stainless steel stent shows up as the orange cylinder. This will be left in place when the catheter is withdrawn

telephone helplines and, most importantly, contacts with local support groups. Some, such as the British Heart Foundation and the Thrombosis Research Institute, play a significant role in medical research, while others such as the British Cardiac Patients Association and the Cardiomyopathy Association direct much of their effort towards supporting patients and their families. Contact details of these and other charities are on the back cover.

Placebos

What help is available for people with heart disease and their families?

A placebo is a dummy treatment with no

The diagnosis of any serious illness is likely to cause great concern, stress and upheaval of normal life patterns. Many questions will arise and will need to be answered, especially in younger people. Often they will be of a personal rather than a medical nature – issues such as diet, sex life, exercise, work and career, sources of financial support, and psychological help when needed. Such questions are outside the scope of this booklet, but some answers may come from GPs and consultants to whom patients are referred. But such people are often very busy and alternative sources of information will be needed.

administered to a control group in a clinical

There are several excellent patient support groups in the UK which can provide leaflets, booklets,

than the placebo.

activity against a patient’s illness and which is

trial. It is given to a proportion of the people taking part, so that comparisons can be made with the active compound that is being tested. The participants do not know whether they have the placebo or the real thing. In order to be considered effective, the experimental treatment must therefore produce better results

13


DIAGNOSIS AND INVESTIGATION OF HEART DISEASE It will now be clear that some symptoms are common to several of the conditions covered in this booklet. Apart from high blood pressure and early atherosclerosis, which often lack symptoms, some form of pain is often frequent. This may range from mild pain on exercising in angina to the severe, radiating pain of a heart attack. Other symptoms include weakness, fatigue, breathlessness on exercise or on lying down, fluid retention in the legs (or lungs in late stage heart failure), changes in the blood pressure in the jugular vein (in the neck), a ‘galloping’ heart, or the irregular heart rhythms of arrhythmia. If your doctor believes you have a heart condition based on these and other evidence such as a highElderly male patient having an electrocardiogram (ECG)

Men undergoing a stress test on an exercise treadmill

risk lifestyle, you are almost certain to be referred to your local hospital cardiology unit, where a cardiologist will arrange for special tests to be carried out. These are not discussed in detail here, but some that you may encounter and their uses are briefly described below. Blood pressure (BP) measurement – the doctor will listen to your heart sounds and may be able to hear turbulent blood flow, indicating damage or poor ejection of the blood. BP measurement in the jugular vein (in the neck) will also be carried out. This is normally done with the patient on a platform at an angle of 30-60o and can provide information about right atrial pressure which, if raised, can indicate right heart failure. Electrocardiogram (ECG) – this is described on page 5. An ECG will normally employ several leads attached to the surface of your body at different locations. The pattern of electrical waves can give much detailed knowledge about the nature of a heart condition, but the traces require expert interpretation. Exercise stress test – An ECG in angina often shows as normal, so an exercise stress test is likely to be performed. This type of test can detect ischaemic heart disease. The patient exercises on a treadmill with gradually increasing effort. As ischaemia develops, pain may be felt and there may be changes in the ECG, heart rhythm and a fall in blood pressure. X-Ray – An X-ray of the chest taken from behind will enable the size of the heart in relation to the lungs and the size of major blood vessels to be assessed. This will give information about the early stages of heart failure. The X-ray may also reveal areas of calcium deposits which are a sign of damage and death of tissue. Angiography – This technique involves the introduction into the coronary arteries of a special chemical which is opaque to X-rays, using a catheter inserted into a vein. This enables the blood vessels to be seen in an X-ray. Areas of

14


narrowing of the arteries due to plaque can be clearly distinguished. Such procedures will be a vital part in preparation for a bypass operation by pinpointing the location of the blockage.

An arteriogram showing a long part of the coronary artery narrowed by atherosclerotic plaque (arrowed)

Echocardiography is the most useful noninvasive technique for studying ventricular performance in the functioning heart and is especially useful in detecting heart failure. It is also used in people with breathlessness associated with heart murmur, some forms of arrhythmia, and MI on the left side of the heart. High frequency ultrasound waves generated by a transducer pass through the body tissue and are reflected from internal surfaces which have different sound-reflecting properties. The reflections are collected by the transducer, which is then able to create an internal image which can be viewed on a screen. In two-dimensional echocardiography, multiple beams are used to build a 2D image of the heart which shows the movement of the parts relative to each other. This is especially useful in the study of valve function. Another type, called Doppler ultrasonography, evaluates the direction of blood flow, its turbulence and speed. The images can be displayed in colour.

An echocardiogram. Though training is necessary to interpret the results, this image shows blood flow through a faulty heart valve

Nuclear imaging – Several scanning techniques may be employed during the investigation of heart problems. In one, gamma scanning, a radioactively labelled chemical is introduced into the blood. A gamma camera then measures the uptake of the radioactivity into the tissues at different levels within the heart. This can potentially reveal areas of ischaemic heart muscle and the extent of healthy blood flow. SPECT scanning uses a synthetic molecule labelled with the radiotracers technetium-99 or thallium201. A three-dimensional scan can be constructed by computer that indicates the volume of heart tissue damaged. Healthy tissue is seen as brightly coloured, while areas of damage remain dark. This information is especially useful in determining saveable areas of the heart before angioplasty or bypass operations. MRI scans give very detailed images and are most suitable for revealing local masses (e.g. tumours) and malformations. Other tests – Blood samples will also be analysed for markers of heart damage, especially in suspected heart attack. A more than two-fold rise in enzymes found in cardiac tissue indicates probable MI. These include creatine kinase MB

(CK-MB) and substances called cardiac troponins. The former rise in four to eight hours, peak at 24 hours and wane by two or three days after a heart attack. The troponins remain elevated for four to eight days.

During angina or a heart attack the heart is deprived of oxygen and nutrients. This gamma scan shows normal blood flow (top), reduced blood flow during an attack (middle) and restoration towards normality as the attack passes (bottom). Red and yellow are regions of good blood flow

15


HEART DISEASE and the pharmaceutical industry The digoxin used today is derived from the cultivation of Digitalis lanata (shown here) rather than the wild foxglove (Digitalis purpurea)

medicine. Around 1919 it was observed that organic mercury compounds used for syphilis caused diuresis and were beneficial in oedema (fluid retention) associated with heart failure. However, the side-effects were considerable and although many organic mercurial compounds were made, they have now passed out of use. The birth of modern diuretic medicines arose from another chance observation, namely that people being treated for rheumatic fever and bacterial infections with sulfa drugs also had increased urine output. In 1949 a sulfa drug was given to three people with marked oedema due to heart failure, and all three showed dramatic improvement. Long-term toxicity was again a problem.

A brief history of medicines discovery for heart disease Most herbal remedies used in antiquity were probably discovered by trial and error. From the earliest times, there was almost no scientific rationale as we would describe it today in the discovery and use of medicines. This situation began to change with the discovery in 1785 that foxglove extract was beneficial in the treatment of fluid retention (dropsy), now recognised as a sign of advanced heart failure. It took another 140 years before the active chemical constituents were identified. As they are chemically difficult to synthesise, they are still extracted from a member of the foxglove family. By the beginning of the twentieth century, the properties of xanthines such as theophylline and caffeine in the treatment of diuresis (an increased production of urine) had been recognised and mercury had assumed a place in human

16

Building on these observations, research chemists prepared modified sulfa drugs, leading to the identification of chlorthiazide, which was even better at reducing both oedema and high blood pressure. They were also safer to use and with further chemical modification led to the introduction of acetazolamide in 1950. This compound was 300 times more potent and soon became the main antihypertensive used. It remains available today. Further advances led to the development of other thiazide diuretics. By the early 1960s loop diuretics with a different mechanism of action had been discovered, followed quickly by the potassium-sparing diuretics such as spironolactone and amiloride, many of which are still a mainstay in the treatment of heart failure. In parallel with these advances, other pharmacologists were unravelling the mechanism of the rise in blood pressure that was observed when extracts of adrenal gland were injected. In 1913 it emerged that adrenaline could cause the constriction of blood vessels or their relaxation, depending on their location. This resulted in the proposal that there may be two kinds of receptors, now named alpha and beta. The latter were to become major players in the design of medicines for heart disease. The first betablockers were identified in 1958 by Sir James Black, for which he received the Nobel Prize for


The mould Aspergillus terreus, from which lovastatin was isolated, growing as a culture in a Petri dish

Medicine. Although the initial compounds had low potency, they quickly led to the identification of the prototype of this class of medicine, propranolol, which remains available today. This was followed by a whole raft of new medicines with slightly differing pharmacological properties. Ultimately, medicines which directly affect ion movement into cells (calcium, potassium and sodium) were found, with uses in the treatment of high blood pressure, angina, arrhythmias, heart failure and myocardial infarction. Apart from the treatment of high blood pressure, the discovery of the beta-blockers had another very important sociological consequence. Before beta-blockers were available, patients only took medicines for conditions (including high blood pressure) when they felt ill. By then, much of the damage had already been done and death rates were high. With well-tolerated beta-blockers, it was possible to treat asymptomatic people – heralding the dawn of preventive therapy. This led to the discovery of other medicines for illnesses with a long development time but without noticeable outward symptoms, such as atherosclerosis, and to the development of preventive screening. The suggestion that medicines that inhibited angiotensin converting enzyme (ACE) might be useful for heart disease came from John Vane, the British scientist who won the Nobel Prize in Medicine in 1982 for his work on aspirin. He discovered that a peptide from the venom of the Brazilian viper (Bothrops jararca) had a strong effect on ACE. He suggested that ACE inhibitors might help control high blood pressure, and though the snake compound did not prove suitable, the programme led to the discovery of the ACE inhibitor captopril (Bristol-Myers Squibb), the first in this new family of medicines. Studies on the mechanism of action of ACE inhibitors revealed in turn the existence of the angiotensin II receptor and led to medicines that can block it. Medicines for treating high cholesterol levels were first identified in the 1950s and early 1960s, but most had unwanted side-effects. The research that eventually led to the statins began in 1971 when microbes began to be tested for chemicals that would inhibit an enzyme involved in the synthesis of cholesterol in the human body. This led to the discovery of mevastatin. Later statins research confirmed the earlier work on mevastatin and went on to isolate a more effective inhibitor, lovastatin, from the mould Aspergillus

terreus. Today there are five statins available in the UK. As we move into the twenty-first century, scientists are turning increasingly away from the traditional therapies for heart disease. Instead, they are beginning to explore the fundamental mechanisms involved and to design new generations of therapy which will probably be an improvement on those currently in use. Some of these newer approaches are discussed in a later section.

Medicines available for the treatment of heart disease and how they work Categories of available medicines and how they work A very considerable range and number of medicines already exists – a clear sign of the progress made over the past 40 to 50 years. Despite this, cardiovascular disease remains the major killer of people in the West and improved medicines are still needed. Table 2 lists the main types of medicine currently available. For many people, the wide variety of medicines for heart disease must appear baffling. Why should compounds that act on the kidneys, liver or intestines play any part in the treatment of heart disease? The answer lies in the fact that the heart is linked by the vascular system (the arteries and veins) to all these organs. Changes in blood flow to the kidneys or the liver can greatly stress or ease the burden of work on the heart. Equally, hormones that bring about secondary effects such as constriction of arterial walls or capillaries in the kidneys may also affect the heart

17


Table 2 Some of the main types of medicine already available for treating heart conditions

TYPE OF MEDICINE

How they work

Used to treat

Diuretics

Act on the kidneys to enhance

Heart failure, high

the excretion of fluids

blood pressure

Angiotensin Converting

Block the conversion of angiotensin 1

Heart failure,

Enzyme (ACE) inhibitors

to angiotensin II [A II]

high blood pressure & MI

Angiotensin II receptor

Block binding sites for A II

High blood pressure,

antagonists Beta-blockers

heart failure Act on beta receptors in the heart,

Heart failure, high blood

kidney and blood vessels, with

pressure, angina

various effects Nitrates

Relax coronary arteries via the

Heart failure, angina

generation of nitric oxide and the redistribution of blood flow Statins Fibrates Amiodarone

Block an enzyme involved in

Atherosclerosis, high

cholesterol synthesis in the body

cholesterol levels

Act on fatty droplets that circulate in

Atherosclerosis, high

the blood and carry cholesterol

cholesterol levels

Modifies the way the body’s cardiac

Arrhythmias

pacemaker works Anti-arrhythmic agents

Modify sodium, potassium and/or

Arrhythmias

calcium movement into and out of cardiac conducting cells Digoxin

Strengthens heart beat by blocking the

Heart failure, atrial

sodium pump, plus some effects on the

fibrillation

vagus nerve Calcium antagonists

Block calcium channels and cause

Angina, high blood

dilation of blood vessels

pressure

Potassium channel

Cause dilation of blood vessels

Angina

openers

and protect heart muscle

and its performance. For these reasons, medicines for heart disease are very varied in type and can often interact with each other to give added benefits. Although this section includes a discussion of how the types of medicine work, it is a simplification of a very complex subject.

Diuretic medicines These are most often used to treat high blood pressure and heart failure. The thiazide diuretics were first introduced for human use in 1958 and still play a major role. As early as 1962, two clinical trials proved the value of lowering blood pressure in the prevention of strokes. Since then, their key role in heart disease has also been

18

abundantly demonstrated. A number of other diuretics find wide application in heart failure, oedema, and angina. They fall into three major groups: the thiazides, the potassium-sparing diuretics and the loop diuretics. Examples are: • Thiazides, e.g. bendrofluazide (Leo, Sovereign), chlortalidone (Alliance), cyclopenthiazide (Novartis, Goldshield), metolazone (Borg) • Potassium-sparing diuretics, e.g. spironolactone, triamterene (Goldshield)


• Loop diuretics, e.g. bumetanide (Leo), torasemide (Roche) and furosemide (several manufacturers). Although most of these medicines have similar uses and properties, some have specific features. For example, torasemide is a long-acting agent which is especially suitable when extended coverage is needed. Most of these compounds are available alone, but many also come in combinations with other heart remedies. However, the combination of diuretics and diuretics with beta-blockers, ACE inhibitors and/or digitalis is complex. In severe heart failure, combinations of thiazide and loop diuretics give superior results. The choice of medicines needs to be tailored to the individual condition – something only your cardiologist or physician can do. Most diuretics act at different sites within the kidneys. In heart failure, the kidney inappropriately reabsorbs water and sodium, which aggravates fluid retention and oedema of the heart and lungs. Diuretics are able to eliminate excess sodium and water through enhanced excretion from the kidneys and are thus able to relieve the symptoms of fluid congestion. This same mechanism also reduces the body’s

water volume and thus reduces high blood pressure as well, an effect that is increased by their dilating action on blood vessels. There are many millions of tubules in each kidney, filtering the liquid as it enters at the glomerulus. The tubule is not a single structure, but can be divided into regions with different fine structures and functions. Some regions absorb only water, while others absorb sodium and potassium ions. Hence the composition of the urine eventually produced by the kidney is very different from the solution entering at the glomerulus. The various classes of diuretic work at different points within the tubules, which accounts for the advantages arising by combining the different types. Three other agents that should be mentioned here, even though they are not strictly diuretics, are acetazolamide (Wyeth) and aminophylline and theophylline (Napp). The first is used for the control of fluid retention and inhibits an enzyme called carbonic anhydrase in the kidney that is involved in fluid and ion excretion. The other two agents also have weak diuretic activity, but they are not widely used today.

Diagram of a kidney tubule, showing the structure and sites of action of diuretic medicines DCT = distal convoluted tubule; PCT = proximal convoluted tubule; CAI = carbonic anhydrase inhibitors; K+, H+, Na+ = potassium, hydrogen and sodium ions; NaHCO3 = sodium bicarbonate; NaCl = sodium chloride

19


Beta-blockers and related compounds Following the discovery of propranalol (AstraZeneca) in the early 1960s, many other beta-blockers have been made available to patients. Studies with these new agents soon made it clear that not all beta-blockers behaved in the same way. In fact, it rapidly became clear that there was more than one type of beta receptor. One group, now called beta1 receptors, is largely located in the heart itself, while beta2 receptors are mainly in the arterial walls and lungs. Some beta-blockers are selective for the beta1 type (called cardioselective) while the beta2 type have a greater effect on the arterial walls and lungs and can induce asthma-like symptoms by Table 3 Some of the many betablockers available for various heart conditions

well as hypertension – including MI and heart failure – as a flurry of new ACE inhibitors has reached the patient. In all, eleven are available in the UK, two of which – moexipril (Schwarz), imidapril (Trinity) – are only licensed for hypertension. The other nine fall into three groups: • active compounds that are further converted by the body into inactive forms – e.g. captopril (Bristol-Myers Squibb) • pro-drugs that are not active until converted by the liver into active forms – e.g. cilazapril (Roche), enalapril (MSD), fosinopril (BristolMyers Squibb), perindopril (Servier), quinapril (Pfizer), ramipril (Aventis) and

Beta selective

Non-selective

Some stimulating action

Atenolol (AstraZeneca)

Labetalol (Celltech)

on beta receptors

Bisoprolol (Merck Pharma)

Nadolol (Sanofi Aventis)

Esmolol (Baxter)

Oxprenolol (Novartis)

Metoprolol (AstraZeneca, Novartis)

Propranolol (AstraZeneca) Timolol (Valeant)

No stimulating action

Acebutalol (Aventis)

Pindolol (Novartis)

on beta receptors constricting the airways. Others interact with both types of receptor to varying degrees and are called non-selective beta-blockers. Both beta1 selective and non-selective betablockers are widely used in heart disease and are further subdivided according to whether they also possess the ability to stimulate some types of beta receptor. Table 3 shows examples of the various types currently available for treating heart conditions. Some other beta-blockers are also used for heart conditions (especially arrhythmias) that combine beta blockade and a degree of blockade of another receptor sub-set called alphareceptors (i.e. they are mixed alpha-betablockers), for example labetalol (Celltech), prazosin (Pfizer) and carvedilol (Roche).

Angiotensin Converting Enzyme [ACE] inhibitors Since the discovery of captopril, much progress has been made into how the angiotensin converting enzyme (ACE) influences blood pressure. This in turn has led to the development of other medicines. The family of ACE inhibitors has assumed an important role in several types of heart disease as

20

trandolapril (Abbott and Aventis) • active compounds that are excreted unchanged – e.g. lisinopril (Bristol Myers Squibb and AstraZeneca). ACE inhibitors have an established place in the treatment of hypertension and some have been shown to reduce the risk of coronary heart disease, stroke, and death. They are prescribed in people with high blood pressure accompanied by heart failure, MI, or kidney problems. Also, longterm ACE inhibition is now common practice in people who have suffered an acute myocardial infarction or who have evidence of poor function of their left ventricles. ACE inhibitors are most often used in combination with beta-blockers, aspirin, statins, diuretics, digoxin or calcium channel blockers. The way in which ACE inhibitors work is now well understood. If blood flow through the kidneys is low, they release a substance called renin, which converts a ‘dormant’ chemical called angiotensinogen into angiotensin I (A I). ACE then converts the A I into angiotensin II (A II). Angiotensin II causes the contraction of blood


ACE INHIBITOR

Angiotensinogen Renin Angiotensin I

AII RECEPTOR BLOCKER (ANTAGONIST)

ALDOSTERONE RECEPTOR BLOCKER

ACE Angiotensin II

Adrenal Gland

AT1 receptor

The reninangiotensinaldosterone pathway. Angiotensin II stimulates both the A II receptor and the adrenal gland to release the hormone aldosterone. Both actions impact on blood pressure and cardiovascular disease. Medicines and where they act are shown in blue

raised aldosterone

Constriction of blood vessels

Long-term heart enlargement

Increased sodium retention in the kidney

vessels (hence raising blood pressure) and also promotes the retention of salt and water (hence aggravating heart failure), partially by stimulating the adrenal gland to release the hormone, aldosterone. Angiotensin II also causes the division of heart muscle cells and fibrosis which, in the long term, can make heart failure more serious. By blocking the conversion of A I to A II, these effects can be eliminated or reduced. Although ACE inhibitors are quite a mature group of compounds and work in a similar way, they are chemically distinct and may behave differently to each other in the body. They are not necessarily interchangeable.

Angiotensin II Receptor Antagonists Rather than preventing the conversion of angiotensin I to angiotensin II, an alternative strategy is to block the receptors to which A II

Increases body resorption of sodium from other organs

binds. This blocks its effects which include constricting arteries and releasing a hormone (called aldosterone) that causes salt and water retention by the kidneys, hence raising blood pressure and, over time, causing heart enlargement. This approach led to the discovery of medicines such as losartan (MSD), valsartan (Novartis) and irbesartan (BMS). These are available for treating high blood pressure in the UK. Valsartan is also licensed to improve survival after MI in clinically stable people with evidence of abnormalities in left ventricular function. All three compounds are also licensed for use in combination with a diuretic. Recent data has indicated that the addition of an A II receptor antagonist to either an ACE inhibitor or a beta blocker can further benefit some forms of heart failure. They are also a valuable

21


A section of an artery showing in simplified form the formation of cholesterol-rich plaque. (purple = plaque; orange = blood clot)

Table 4 Ideal and ‘at risk’ levels of total cholesterol, LDL -cholesterol and HDLcholesterol. Figures are in millimoles per litre.

Total serum cholesterol

5.2 5.2-6.2 Over 6.2

Ideal Borderline High risk

LDL – cholesterol (‘bad’ cholesterol)

3.4 3.4-4.1 4.2-4.8 Over 4.9

Ideal Borderline High risk Very high risk

HDL – cholesterol (‘good’ cholesterol)

1.6 Less than 0.9

Ideal Some risk

alternative for people who, for one reason or another, cannot tolerate ACE inhibitors.

22

cholesterol poses a risk.

Medicines acting on cholesterol (statins, fibrates, nicotinic acid-type)

LDL-cholesterol blood levels correlate directly with coronary heart disease events, thus emphasising the importance of reducing it.

Cholesterol is essential for the maintenance of the health of cell membranes throughout the body. It can be made by all cells, but mainly arises in the liver and from our diet. However, cholesterol is also a component of plaque and an excess of it is one of the most important risk factors for atherosclerosis and coronary heart disease. Physicians recognise different levels of risk for the different types of cholesterol, as shown in Table 4. Too much LDL-cholesterol or too little HDL-

A number of medicines and dietary additives have been developed which help regulate cholesterol, such as the statins, fibrates and nicotinic acid. In addition, changing the balance of fatty acids in the blood has proved beneficial in people who have already experienced a first heart attack. Solvay Pharma markets a highly purified fish oil containing 90 per cent of EPA and DHA, two omega-3 polyunsaturated fatty acids. Extensive trials showed that this treatment could reduce


deaths in this group of patients. There has also been much recent interest in the plant stanols which are added to butter substitutes and are now available in most supermarkets for helping to control cholesterol. Although the early statins, mevastatin and lovastatin, which were isolated from extracts of the moulds, Penicillium citrinum and Aspergillus terreus, are no longer available as medicines, they gave rise to a huge amount of discovery chemistry. Three broad approaches were employed, each aimed at producing more effective and better tolerated medicines. The result has been the five statins currently available in the UK: • synthetic compounds made entirely in the laboratory: fluvastatin (Novartis); atorvastatin (Pfizer), rosuvastatin (AstraZeneca) • the introduction of small chemical changes into fungal-derived products: simvastatin, (MSD)

• biotransformation, in which natural statinlike molecules are modified by adding them to microbial cultures – pravastatin (BMS) The biochemical step by which statins achieve their cholesterol-reducing effect was well understood even before the inhibitors were identified; in fact, the search for inhibitors was based on earlier discoveries concerning the way in which cholesterol was made and processed by the human body. To appreciate how statins act, it needs to be realised that cholesterol arises from two sources, our diet and new cholesterol made in the liver. Cholesterol in the liver is made by the conversion of the starting material, acetyl coenzyme A (Acetyl-CoA). This is brought about by a chain of reactions. Statins are able to block an important initial step and thus prevent the formation of cholesterol. In addition, statins have the important property of increasing the number of LDL-receptors in the liver, thus helping remove Simplified diagramme of fat and cholesterol metabolism showing where lipidlowering medicines work. FFAS= free fatty acids

23


Table 5 The fibrates currently available in the UK, their manufacturers and their action

COMPOUND

MAKER(S)

ACTION

Benzafibrate

Link Pharma & Roche

Lowers LDLs by accelerating their breakdown and reduces cholesterol production

Ciprofibrate

Sanofi Aventis

Lowers LDLs and VLDLs and increases HDLs

Fenofibrate

Fournier

As for Ciprofibrate

Gemfibrozil

Pfizer

Reduces high levels of some fats, cholesterol, LDLs and VLDLs, and raises HDLs.

LDL-cholesterol from the blood. Other lipid-modifying compounds are prolongedrelease nicotinic acid (Merck Pharmaceuticals) and acipimox (Pfizer), which inhibit the release of fatty acids and reduce the level of VLDL by up to 20 per cent. They also inhibit the conversion of VLDL to LDL and increase the level of HDL. Fibrates act to decrease the amount of LDLs and VLDLs (carriers of ‘bad’ cholesterol) but increase the level of HDLs (carriers of ‘good’ cholesterol) that circulate in the blood and carry the cholesterol to other tissues. Some are also able to reduce the production of cholesterol in the tissues. This ‘dual action’ is also a property of some so-called ‘third generation’ statins, such as rosuvastatin, which can both block cholesterol synthesis and reduce LDL levels to the clinical target in 70 per cent of patients. Prescription of statins in England from 1998/99 to 2002/03

Other compounds that help reduce cholesterol do so by blocking its uptake from the intestines. Ezetimibe (MSD and Schering-Plough) can do this, though it is only used for people with a family history of high cholesterol levels. Other agents acting in the gut, such as cholestyramine (Pliva), are called bile acid sequestrants. These trap bile acids secreted from the liver which contain cholesterol. Normally, these are reabsorbed and recycled, but by blocking their absorption, the liver has to make new molecules. This uses up its stores of cholesterol, resulting in a lowering of cholesterol levels in blood via uptake through the

Number of prescriptions for statins (m)

20 18 16 14 12 10 8 6 4 2 0

24

Although the fibrates (Table 5) have been around a long time, several are still in use, especially in people with a predisposition towards abnormally high fat and cholesterol levels. They aim to reduce LDL-cholesterol levels in the body.

1998/99

1999/00

2000/01

2001/02

2002/03


LDL receptors. Once again, these are used mainly in people with certain specific lipid disorders where trials have shown that they can significantly reduce the risk of fatal and non-fatal MI. They are often used in combination with statins. It is important to emphasise that the use of these various lipid-lowering medicines is only advocated once other risk factors have been addressed. These are mainly life-style issues such as smoking, alcohol intake, obesity, diabetes and exercise. However, prescriptions for statins have risen steadily and one, simvastatin, has recently been made available for purchase without a prescription.

Agents that prevent platelet aggregation or disperse blood clots

of aspirin was discovered and the era of antiplatelet agents began. Even so, it took until 1994 and many clinical trials before its true advantage in reducing further heart events by up to 25 per cent was established. Other APAs such as clopidogrel became available, to be followed by eptifibatide and tirofiban. These last two, called GP IIb/IIIa receptor blockers, act somewhat differently by blocking the site on platelets that allows them to stick to fibrinogen and other blood factors. Interestingly, eptifibatide was designed after the isolation of a compound from the venom of the South-eastern pygmy rattlesnake – a creature little bigger than an English slowworm. Recent studies suggest that eptifibatide can significantly reduce the risk of death within 30 days of an MI. In late 2002 the UK’s National Institute for Clinical Excellence (NICE) issued updated

Although the statins aim to prevent plaque buildup, many sudden disorders of the heart are caused by plaque splitting to reveal the underlying surface. The exposure of this surface allows contact with blood platelets and the release of clotting factors. As a result, the platelets are triggered to form blood clots. As this occurs, a series of blood proteins are activated which ultimately convert fibrinogen into a network of fibres (fibrin) which binds the clot together. This process can severely restrict or block the artery, with dire consequences for the patient. Other approaches utilise medicines that prevent blood clot formation, either by reducing platelet stickiness or by blocking the protein clotting cascade. However, a balance has to be struck between achieving the required effect and ‘overthinning’ the blood, resulting in unwanted bleeding. This has led to the introduction of antiplatelet agents (APAs) such as dipyridamole (BoehringerIngelheim), clopidogrel (Sanofi Aventis), eptifibatide (Schering-Plough), tirofiban (MSD) and abciximab (Lilly) and medicines that help dissolve blood clots (called fibrinolytics or thrombolytics). In this last group are alteplase and tenectaplase (Boehringer-Ingelheim) and reteplase (Roche). They have applications variously in unstable angina, atrial fibrillation and acute MI. One well-known agent that has anti-platelet activity is aspirin. As long ago as the 1950s, a Californian doctor noticed that people taking aspirin appeared to be protected from heart attack. Some years later, the anti-platelet activity

Above: Diagrammatic representation of clot formation showing platelets and fibrinogen strands

Tangled strands of fibrin entrapping red blood cells

25


The southeastern pygmy rattlesnake which provided the starting point for the discovery of eptifibatide

guidance for the use of these compounds and recommended their use (in addition to aspirin and the anti-coagulant heparin) for the initial medical management of patients with unstable angina or mild heart attack who were at high risk of a further attack or death. Another entirely different compound with GP IIb/IIIa activity is abciximab (Lilly). The end stage of the steps in platelet aggregation in clot formation occurs when they become bound together by tangles of fibrin. This is brought about because specific regions on the fibrin chains recognise binding sites on the platelets and stick to them. Abciximab is an example of a monoclonal antibody, a protein made by genetic engineering that can recognise and bind to this same specific site – the GP IIb/IIIa site – and in so doing prevent the fibrin binding and the clot consolidating. At present, this medicine is mainly used during ‘remote’ surgery immediately following a heart attack. Two other medicines which affect blood clotting are called low molecular weight heparins: enoxaparin (Sanofi Aventis) and dalteparin (Pfizer). Heparin is a naturally occurring substance that helps prevent unwanted blood clotting by neutralising the action of a blood protein called Factor Xa. Both have advantages over the natural compound and are viewed as a significant advance in the treatment of unstable angina. They are also used in preventing deep vein thrombosis and some forms of heart attack.

Heart muscle viewed in the electron microscope. The circular structures are mitochondria (energy stores). The thick grey bands are the Z-bands which move towards each other on contraction as the actin fibrils slide between the myosin fibrils

Calcium antagonists

Myosin filaments

z

z

• those with a specific action on heart tissue such as diltiazem (Napp) and verapamil (Abbott), termed Class I calcium antagonists

Movement of Zbands as heart beats Actin filaments

z

Calcium plays an important role in the regulation of cell function and is the main ion channel regulator of heart muscle contraction and heart beat. Several medicines (the calcium antagonists) have been devised that modify calcium uptake into heart and blood vessels by interacting with various binding sites in the calcium channels. They currently fall into two main groups;

z

• those acting mostly on the smooth muscle of blood vessels mainly outside the heart such as amlodipine (Pfizer), felodipine (AstraZeneca), nicardipine (Yamanouchi), nifedipine (Bayer) and nisoldipine (Forest) – termed Class II calcium antagonists. Class I medicines can reduce both heart rate and

26


the force of heart muscle contraction, while those of Class II ‘relax’ arterial blood vessels, thus reducing the resistance to the flow of blood. These properties reduce the work load on the heart and hence its demand for oxygen and energy. Because of these actions, both types are used in the treatment of stable angina, though diltiazem and verapamil are available as secondline treatments for unstable angina as well. Some of these medicines have been prepared as special slow-release forms, or only need to be taken once every 24 hours.

have to be avoided. Hence, the choice of medicine and any combination has to be made by a specialist.

Although some of these products can be used in combination with other heart medicines, there are some possible undesirable interactions that

Medicines with anti-arrhythmic activity have been classified by dividing them into four types called Class I, II, III, and IV. In this section, we will

Anti-arrhythmic agents Irregularities in heart rate can take many forms, from mild palpitations to life-threatening ventricular fibrillation. These arise because of errors in the regulatory electrical signals generated to control heart beat or due to damage (for example after MI) to the pacemakers or conducting fibres themselves.

Triggering a heart beat. Calcium floods into heart cells through the calcium channel at each beat which releases internal stored calcium (blue arrows). This causes the muscle to contract. Three calcium channel blockers act at different sites in this calcium channel. There are also sodiumpotassium channels where digoxin acts and a separate sodium-calcium exchange channel.

27


have failed to respond to other therapies.

Electrocardiogram (ECG) showing atrial fibrillation in the heart of a 78 year old man. In this condition the heart muscles contract without synchronisation.

Other agents Nitrates: The first true medicine of this type was

mainly be concerned with Classes I and III. Class II agents fall within the beta-blocker group described above, some of which are useful in treating arrhythmias. These include atenolol, metoprolol, and propranolol (AstraZeneca), nadolol (Sanofi Aventis), oxprenolol (Novartis), esmolol (Baxter) acebutolol (Aventis) and sotalol (Celltech). Class IV agents are calcium antagonists which can modify heart beat by their action on calcium uptake into cells, notably diltiazem (Napp) and verapamil (Abbott). Class I medicines act by blocking channels that transport sodium. This changes the rate at which electrical charge builds up in the pacemaker and thus the rate at which it ‘fires’. Older compounds in this group – quinidine (AstraZeneca), procainamide (BMS), disopyramide (Borg) – are most useful for treating very rapid heart rates arising in the atria. By contrast, mexiletine (Boehringer Ingelheim) and flecainide (3M Pharmaceuticals) are more useful for rapid ventricular rates which may arise after MI. It is interesting that although these compounds can slow a rapid heart beat, they do not prevent the heart from beating at or close to the normal rate. Propafenone (Abbott) combines anti-arrhythmic activity with some beta blockade and has application in both atrial and ventricular arrhythmias. Fifty per cent of patients who did not respond to flecainide still responded to propafenone treatment, presumably reflecting a difference between these two Class I medicines in the way they work. Currently, only one Class III anti-arrhythmic is available, amiodarone (Sanofi Aventis) but it has an important place in the management of arrhythmia. It has a very slow onset of action (several weeks) and its exact mode of action is not clear. However, it can prolong the time of signal discharge from the pacemaker and thus slow rapid heart rate. It is useful for a variety of atrial and ventricular rhythm disorders in patients who

28

glyceryl trinitrate (or nitroglycerin) – the ‘tablet under the tongue’. It is given by this route because when it is swallowed, it is quickly absorbed and destroyed by the liver. This compound remains in use today and many efforts have been made to increase its quite short duration of action. These include specially developed forms that deliver the medicine over a period of time including skin patches, sustained release under-the-tongue tablets, sprays, and ointments, variously available from Forest, 3M Pharmaceuticals, Novartis, Pliva, Schwarz and Schering-Plough. As an alternative, chemical modifications to nitroglycerin have been made, resulting in medicines that can be taken by mouth and with a longer survival time in the body. These include isosorbide mononitrate and isosorbide dinitrate (Schwarz) which are of value in patients requiring a more extended anti-angina action. All these agents work promptly because they generate nitric oxide, which acts directly on the smooth muscle of the heart and on the coronary arteries to relax them. This eases blood flow, so that the heart’s work-load is rapidly reduced, oxygen demand falls and the angina pain eases. Unfortunately, ‘nitrate tolerance’ can develop, especially with long-acting preparations and the compound appears to become less and less effective. This is dealt with by gradually reducing the dose to give a nitrate-free period during which sensitivity returns.

Warfarin: This has been a very widely used oral medicine for the prevention of blood clot formation. It was discovered in the USA as a result of investigations into animal poisoning after cattle had eaten spoiled sweet clover hay. These studies led to the identification in the hay of dicoumarol (a weak anti-coagulant) and then to its chemical modification to the more powerful agent, warfarin (Goldshield). Warfarin acts by reducing the levels of vitamin K in the liver which are part of the blood-clotting mechanism. Because some vitamin K is stored in the liver, warfarin takes from two to seven days to start working and so cannot be used when emergency anti-coagulation is required. Though


less popular today, it may still be prescribed during the first three to six months after a heart attack and to treat atrial fibrillation in which there is a much increased risk of unwanted blood clot formation.

Adenosine: This nucleoside analogue (Sanofi Aventis) is widely used for treating some serious ventricular arrhythmias. It acts through several mechanisms, one of the most important of which is the opening of potassium channels, especially in the atrioventicular node.

Digoxin: Based on the cardiac glycosides present in the foxglove, digoxin (GSK) is available for a number of heart conditions. These include chronic heart failure with or without atrial or ventricular arrhythmias or flutter. It works by indirectly increasing the calcium concentration inside heart cells, which strengthens the heartbeat.

Nicorandil: This is a potassium channel stimulator available from Sanofi Aventis with the ability to dilate the large coronary arteries. It is also thought to have some nitrate-like properties and is recommended as second-line treatment for angina.

Dobutamine: This agent from BoehringerIngelheim stimulates beta1 receptors in the heart which has the effect of increasing heart rate. It does so without increasing blood pressure. Its main use is in supporting heart function in heart failure.

Hydralazine: This relatively old compound (Sovereign) acts as a vasodilator (i.e relaxing blood vessel walls). It is sometimes added to diuretics and digitalis-type medicines in moderate to severe heart failure.

Milrinone: This belongs to a group of compounds called cardiotonics, most of which are now discontinued. Milrinone (Sanofi Aventis) has properties like digitalis and increases the force of the heart beat and has some ability to relax blood vessels. Used in severe congestive heart failure, this compound inhibits an enzyme called phosphodiesterase-III (PDE-III) thereby increasing, in the short term, the amount of energy available to the heart. Taken as a whole, the above categories of medicines have resulted in a considerable reduction in death from heart disease.

Agents in development related to conventional medicines Currently, there are no new diuretics or betablockers in clinical development, probably indicating that nearly all avenues in these mature classes of medicines have now been explored. However, there are ACE inhibitors, A II antagonists, a single calcium antagonist, a statin and an antiarrhythmic in trials and these are discussed briefly below. Also clopidogrel (BMS, Sanofi Aventis) is in trials for MI and fibrillation. Though ACE inhibitors are a well-established group of medicines, omapatrilat (BMS) is in late phase development for high blood pressure and heart failure. Omapatrilat appears to differ from some other ACE inhibitors in that it possesses dual action, by inhibiting ACE and also an enzyme in the kidney and atrial wall called neutral endopeptidase (NEP). This is an interesting mechanism, as NEP can increase the breakdown of a substance that helps remove excess water and salt from the body. However, some problems with tolerance have been encountered with omapatrilat in clinical trials and its real clinical benefit has still to be proven. New angiotensin II receptor blockers remain an area of considerable interest and four are currently in development. Candesartan (Takeda), irbesartan (Sanofi Aventis and BMS), valsartan (Novartis) and TCV-116 (Takeda) are all in latestage development for heart failure. Candesarten and irbesartan are already licensed for hypertension but studies have now demonstrated real survival benefit in heart failure and advanced trials are now in progress. Irbesartan is also in clinical trials in atrial fibrillation. A modulator of calcium uptake which appears to work by blocking the exchange of sodium for calcium in the damaged heart is also in development – MCC-135 (caldaret, Takeda). Early studies in MI have been promising and Phase 2 trials have now begun in the USA and Europe. One additional statin is in early clinical trials. This is pitavastatin (Sankyo Pharma) which, like the others, also inhibits cholesterol formation. However, recent studies have shown that it also induces nitric oxide production by the cells which line our blood vessels (vascular endothelial cells), thus relaxing them. It may also help protect them from inflammatory factors such as tumour necrosis factor alpha. This in turn may help minimise plaque formation, though such action

29


2000

Deaths Prevented or postponed

Estimates of the deaths prevented or postponed by medicines in England and Wales in the year 2000.

1800 1600 1400 1200 1000 800 600 400 200 0

Thrombolysis

B-blockers

ACE inhibitors

Low estimate

has still to be shown in the clinic. Of the antiarrhythmics, dronedarone (Sanofi Aventis) has reached Phase 3 development for atrial fibrillation – the most common sustained

A bone marrow stem cell

30

Statins

Best estimate

Warfarin

Aspirin & Heparin

Platelet lla/lllb inhibitors

Highest estimate

disorder of heart rhythm. A series of trials has shown the efficacy of dronedarone in preventing the recurrence of atrial fibrillation in susceptible patients.


NEW DEVELOPMENTS and future directions The next decade and beyond are likely to see the introduction of entirely new approaches to the treatment of heart disease. This is because continuing research into mechanisms have revealed new possible targets for medicine design and intervention. In some senses we are moving from treating WHAT happens in heart disease to address the question of WHY it happens and in so doing seeking to modify the underlying disease process. Some of these new avenues have already reached early clinical trial stage. These newer approaches are grouped under the different heart conditions.

Atherosclerosis and hyperlipidaemia Several new approaches aimed at modifying cholesterol and lipid balance in the body are under investigation. These potential medicines with their rather complex names are discussed briefly here. They include: • Lp-PLA2 – Lipoprotein-Associated Phospholipase A2 inhibitors • PPAR – Peroxisome Proliferator Activated Receptor stimulators • CETP – Cholesteryl Ester Transfer Protein inhibitors. During the development of atherosclerotic plaque, the tissues can become inflamed. GlaxoSmithKline is investigating the possible role of the enzyme called Lp-PLA2 in this inflammation. It has developed a compound that blocks Lp-PLA2 action, thus reducing arterial and heart risk by targeting the inflammation in the plaque. The compound (480848) has entered early clinical trials. GSK is also developing two compounds which act as stimulators of two different sites on the PPAR, GW-501516 and GW-590735. Interest in this area arose because a compound used to treat diabetes (rosiglitazone) was shown to benefit both hypertension and vascular function. It is also a known stimulator of PPAR, thus suggesting that

PPAR may be involved in some aspects of atherosclerosis. This idea is supported by the discovery that PPAR is present in both the walls of blood vessels and in the cells lining them. Both compounds are in early clinical trials. Pfizer has been exploring CETP inhibitors, which had been proposed as a means for improving the cholesterol balance in atherosclerosis. CP-529414 (torcetrapib) has demonstrated a significant increase in the amount of HDL-cholesterol (‘good’ cholesterol) and a lowering of the levels of LDLcholesterol (’bad’ cholesterol) when used alone and in combination with a statin. It has now entered Phase 3 trials. Another product acting on cholesterol, BO-653, is being developed by Chugai Pharma. This specially designed molecule is called an anti-oxidant and is thought to work by preventing the oxidation (i.e. partial breakdown) of LDLs which are thought to play a major role in the accumulation of cholesterol in developing plaques. It specifically targets the LDLs rather than HDLs and is well distributed in aortic blood vessels. This is an important distinction, as some earlier antioxidants failed in the clinic because they affected both LDLs and HDLs. BO-653 has now progressed to Phase 2 clinical trials. Clearly, these approaches could provide additional weapons in the fight to control cholesterol and fat balance and have the potential to benefit many people at risk from atherosclerosis.

Angina and Myocardial Infarction There are few new medicines in development for angina, though Servier has progressed ivabradine to Phase 3 trials. It acts selectively to reduce heart rate, maintain muscle contraction in the ventricles, and improve electrical signal spread within the heart. By contrast, there are several experimental approaches being assessed for MI, especially compounds which attempt to reduce further heart attacks or damage after a first heart problem.

31


Ximelagatran (AstraZeneca) blocks the action of thrombin, another of the many proteins involved in blood clot formation. When given with aspirin in early trials, it proved more effective than aspirin alone in reducing the number of problems (including deaths) after a heart attack. The relative risk was reduced by 24 per cent. Registration is still pending in the UK. Another oral agent which works in a similar way is dabigatran (Boehringer-Ingelheim). Although it is being assessed for the prevention of blood clots following hip and knee replacement surgery, it is also in Phase 2 trials for the prevention of atrial fibrillation. Both ximelagatran and dabigatran may eventually prove useful after a heart attack as warfarin replacements. Pexelizumab (Procter & Gamble) is a monoclonal antibody directed against a blood protein called complement 5a (C5a). It has been shown that activation of C5a during cardiac events causes inflammation that contributes to cellular and tissue damage. An intravenous dose of pexelizumab can block C5a’s action for up to 24 hours, thus limiting damage after a heart attack. Initial studies with the medicine tried to assess whether it would reduce the size of the area of tissue damage, but this could not be shown. However, it emerged that survival was improved at 90 days after a heart attack – an improvement still evident after six months. Further studies are continuing, including the possible role of pexelizumab in bypass surgery. Cariporide (Sanofi Aventis), a new selective inhibitor of hydrogen ion exchange, has been shown to reduce the area of damage after an ischaemic event. It also reduced the signs of developing heart failure. Cariporide remains at the pre-clinical stage.

Heart failure The past decade has seen a big increase in research into heart failure as the final stage in many heart disorders. The result has been the discovery of several new compound types, some of which have now entered clinical trials. The most advanced agent, already available in some European countries, is levosimendan (Abbott) – a calcium ‘sensitiser’. It is awaiting approval in the UK. This has an unusual and dual mode of action. It appears to be able to enhance the power and duration of heart muscle activity in the presence of calcium by causing the heart

32

muscle proteins (actin and myosin) to contract. It does so without increasing calcium levels inside the heart cells and so is less likely to cause arrhythmias than calcium channel openers. It simultaneously opens potassium channels on blood vessels, causing them to open (dilate), with an easing of blood flow. This dual action has been called ‘inodilator’ action and has the effect of correcting blood flow abnormalities in heart failure, reducing lung congestion and improving flow through the arteries. GlaxoSmithKline is developing nesiritide, a genetically engineered form of a human hormone called hBNP (human B-type Natriuretic Peptide). This hormone has effects on the interrelationships between the heart and the kidneys, acting on the re-absorption of sodium and water, sodium excretion, and urine output and inducing balanced dilation of both arteries and veins. These properties and the raised levels of hBNP seen in patients with heart failure suggest that the hormone plays a role in the body’s natural compensatory mechanism in a failing heart. The hormone aldosterone, part of the angiotensin I and II system, also contributes to the body’s water and salt balancing mechanisms. It has actions on the heart itself and can contribute to heart enlargement and tissue damage. Clinical studies have shown that ACE inhibitors and A II antagonists do not block the actions of spironolactone adequately, suggesting that other specific blockers of this hormone might be useful. Spironolactone acts on the aldosterone receptors, but its usefulness is limited, because it also binds to several other steroidal receptors, causing unwanted side-effects. Scientists at Pfizer have developed a medicine to block this receptor selectively – called a Selective Aldosterone Receptor Antagonist (SARA), and as a result identified eplerenone, which is now licensed for heart failure following myocardial infarction. Five other medicines mentioned previously have potential in more than one heart disorder, namely candesartan (Takeda), caliporide (Sanofi Aventis), valsartan (Novartis), caldaret (MCC-135, Takeda) and ivabradine (Servier). Candesartan and valsartan belong to the A II receptor antagonist group and have been available for high blood pressure for several years. Their use in this area has also shown a beneficial effect in heart failure. Studies suggest a possible effect on cardiac gene expression, which may contribute to its heartprotecting action. Caliporide has shown benefit in model studies of heart failure, but is still at the


Coloured x-ray of an enlarged heart, the expanded part overlaying and obscuring the left lung lobe and a sure indication of heart failure

pre-clinical level, while caldaret has also entered Phase 2 trials in heart failure. Ivabradine may also have uses in heart failure. Four further compounds are in development for heart failure, acting in three different ways, namely: • CVT-124 (Biogen Idec), a blocker of the adenosine-A1 receptor • SR-121,463, (Sanofi Aventis) and conivaptan (Yamanouchi), both blocking the vasopressin receptor • Daglutril (Solvay Healthcare) a mixed inhibitor of endothelin converting enzyme and neutral endopeptidase

CVT-124 (Biogen Idec) binds to and blocks a specific site called the adenosine A I receptor. It has been shown to maintain kidney function in heart failure patients while not adversely affecting sodium excretion. The results of Phase 2 trials suggest that it reduces oedema in people with stable heart failure. Two other new compounds act on the vasopressin system. Vasopressin (otherwise known as antidiuretic hormone) causes the constriction of small arteries, thus raising blood pressure. It also decreases urine excretion. Both these effects have the potential to aggravate heart failure. Clinical studies added weight by showing that vasopressin levels were raised in heart failure patients. Hence the search began for medicines that block the vasopressin binding sites, of which there are at least three sub-types. Conivaptan (Yamanouchi) has been shown to block two of the three receptors and to increase urine output. Phase 2 trials in patients with heart failure have been satisfactory with an increased urine output and a better sodium blood level. Phase 3 studies are planned. Sanofi Aventis has also developed a vasopressin antagonist known as SR-121,463, which is selective for just one of the receptor sub-types. Studies in heart failure patients have shown a dose-related increase in urine output with no disturbance of blood ion balance. Phase 2 trials are in progress. Daglutril (Solvay Healthcare) has a dual action, as it inhibits both endothelin converting enzyme (ECE) and neutral endopeptidase (NE). ECE is an important enzyme in the regulation of the tone of arterial walls (i.e. whether they are relaxed or firm), while NE can increase the breakdown of a

substance that helps remove excess water and salt from the body. These may work together to give additive effects. This compound is in phase 2 trials.

Arrhythmia Several agents are in development for the treatment of arrhythmia. Three work by blocking the potassium channels into heart cells (which have two binding sites). They are tedisamil (Solvay Healthcare), azimilide (Procter & Gamble) and AVE-0118 (Sanofi Aventis). Tedisamil combines antiarrhythmic action with a degree of anti-ischaemic activity. It has been shown to slow the heart rate and benefit people with ischaemic heart disease and angina. The company which makes it is now focusing its efforts on atrial fibrillation, and the medicine has now entered Phase 2/3 clinical trials for this indication. Azimilide differs from other potassium channel blockers in being specific for just one of the two binding sites, known as ‘IKs’. Compounds that block the other site (IKr) have been shown to stop arrhythmias in some circumstances, but also have a high (and potentially serious) risk of triggering arrhythmias. So far, azimilide has been free of this unwanted effect and it may be an effective therapy for atrial fibrillation in patients with depressed left ventricular function. Further studies are planned. AVE-0118 has entered Phase 2 trials. Piboserod (GSK) appears to act as a specific antagonist of one of the receptors for 5hydroxytryptamine, the 5-HT4 receptor. GSK has suggested that blockers at this site may have use in arrhythmia, as well as some unrelated diseases. Piboserod is currently in Phase 2 clinical trials.

33


Finally, dronedarone (Sanofi Aventis) is in Phase 3 trials as a possible replacement for amiodarone, a Class III antiarrhythmic medicine. Amiodarone is already recognised as an important medicine for arrhythmia, but it is not free of side effects, including an occasional tendency to cause ventricular arrhythmias. This has restricted its use, often limiting it to a hospital setting. Dronedarone was in two Phase 3 trials during 2004 and so far it has not shown the adverse effects of amiodarone. However, there were some safety questions in a third trial in patients with heart failure. Sanofi Aventis has a follow-up compound in the same class, SR-149,744.

The future It will be clear from this extensive array of new compounds that the range of therapeutic options in heart disease could change substantially within the next few years. This, coupled with improved

life-style and behaviour, will continue to reduce the unnecessary illness and deaths associated with heart disease. However, new and better medicines will still be necessary and new targets for medicines design are constantly being found. For example, calcium, as the currency of heart muscle activity, is receiving much attention. In particular, companies are looking at the proteins that shunt calcium backwards and forwards (cycling proteins) between the actin and myosin contractile microfilaments and the intracellular membranes at each heart beat. These provide attractive targets, but specific compounds have still to be designed and made. Other scientists are unravelling the pathways involved in the action of HIF (hypoxia-inducible factor) which is involved in gene activation. It is proposed that medicines that modify HIF may have activity against ischaemia and some other conditions.

HOW MEDICINES ARE LICENSED

34

1

Initial research on new compounds is carried out in the laboratory, using a wide variety of techniques.

2

Promising compounds are then studied in animals, under strict ethical and legal conditions, to investigate effects that currently cannot be predicted from computer and test tube studies.

3

A sequence of phases of clinical assessment in humans follows strict guidelines: •

Phase 1: a small number of healthy volunteers, sometimes patients, is given the compound. These trials will determine some aspects of how it works in humans and help to establish the dose required.

Phase 2: a small number of patients with the condition are given the medicine to assess both that it works and check that it does not produce unacceptable side effects.

Phase 3: many more patients, perhaps several thousand, take the medicine under appropriate supervision for an appropriate period. It is tested in comparison with an established compound and/or a placebo. These studies are used to establish the efficacy of the new medicine. If the results prove satisfactory in terms of quality, efficacy and safety, the data gathered are presented to the medicines evaluation authorities. If the evidence satisfies the authorities, a marketing authorisation (a licence) is issued.

Phase 4: the newly-licensed medicine is studied in large numbers of patients in general practice to assess its clinical effectiveness and safety in general use.

4

SAMM (Safety Assessment of Marketed Medicines) studies are sometimes initiated after the medicine has been made available for doctors to prescribe and to help identify any unforeseen side-effects. These may involve many thousands of patients.

5

GP databases are also used to identify medicine safety issues and to explore the potential for new and better uses of medicines once the product is available for prescription.


So far, gene therapy has been a disappointment at the clinical level, but some companies are examining the possibility of repairing defective genes present in the cells lining blood vessels. The attraction is that these cells are readily accessible – genes in appropriate carriers can be injected into the blood stream and immediately contact their target cells. This accessibility has also raised the prospect of a vaccine for atherosclerosis and early laboratory studies are in progress. Meanwhile, two interesting observations have been made regarding the medical potential of stem cells in cardiovascular medicine. Firstly, both blood and bone marrow stem cells have been shown to contribute to the formation of new blood vessels in the human adult. Secondly, stem

cells from the recipient migrate into newly transplanted donor hearts. This raises the possibility that embryonic or bone marrow stems cells might be mobilised or transplanted in order to promote the repair of existing heart damage. Clinical studies have indicated new tissue formation and improved function in stem cell recipients after a heart attack. Laboratory studies also show that embryonic stem cells can be made to develop into certain types of myocardial cells and have been proposed as possibly suitable agents for restoring cardiac function. So although still the stuff of science fiction, stem cell therapy may one day offer hope for genuine restorative therapy in people with seriously compromised heart function.

CONCLUSIONS Medicines for heart disease must go down as one of the great success stories for the pharmaceutical industry in the twentieth century. Entire families of diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, statins, anti-platelet agents, calcium channel modulators and antiarrhthymics are now widely available. Some of these, such as beta-blockers and statins, have even heralded an era of preventive treatment based on screening for clinically ‘silent’ conditions such as hypertension and raised cholesterol. So it is ironic that cardiovascular disease remains one of the greatest health problems in society today. It continues to cause many premature deaths and to seriously erode the quality of life of many of our older citizens. One reason for this is undoubtedly our increased life expectancy, and medicines may have become a victim of their own success in making a positive contribution to this trend. In 1900 a 65 year old woman could expect 11.3 years of life; by 2000 this had risen to 18.9 years. Corresponding figures for men are 10.3 and 15.8 years. A second reason hinges around lifestyle. It is well established that a poor diet, lack of exercise, smoking and excess alcohol increase the risk from cardiovascular disease, obesity, diabetes and

some cancers. The wider adoption of a healthier lifestyle would undoubtedly make further inroads into the illness and deaths caused by cardiovascular diseases. Changing lifestyle is a long-term goal. For now, diseases of the heart and circulation continue to pose major challenges and demand new and better medicines. This has required a refocusing of R&D away from the traditional approaches to address the underlying mechanisms shaping the disease process. The results are now coming through, and many compounds are in trials to test the underlying assumptions in their design. Further off, other new targets are emerging from research. Whole new technologies are also being explored, such as gene and vaccination therapy and the use of stem cells to repair damaged heart tissue. The message for the future is a good one. We can each do a great deal on our own behalf to avoid heart disease in the first place, but if we are unlucky enough to fall victim to it, then never before has there been such an array of powerful and selective medicines, high-tech diagnostic methods, or skilled surgical procedures for heart disease as there is today.

35


MARKETED AND EXPERIMENTAL MEDICINES FOR THE TREATMENT OF HEART DISEASE This list does not include many of the medicines mentioned in tables in the main text Product

Product

Target

Company

name/number

type

disease

Abbott

Levosimendan

Calcium sensitiser plus K channel activator

HF

Propafenone

Anti-arrhythmic (Cl.1)

Arrhythmias

Verapamil

Ca antagonist (Cl.1)

Tachycardias & angina

Rosuvastatin

Statin

Atherosclerosis & hyperlipidaemia

Candesartan

A II receptor blocker

HF

Propranolol

NS beta-blocker

Arrhythmias & angina

Quinidine

Anti-arrhythmic (Cl.1)

Arrhythmias

Ximelagatran

Anti-coagulant

Atrial fibrillation

Felodipine

Calcium antagonist (Cl. 2) Angina

AstraZeneca

Bayer

Nifedipine

Ca antagonist (Cl.2)

Biogen Idec

CVT-124

Adenosine A antagonist HF

Boehringer-Ingelheim

36

PC

I

2 3

L

Comments Available in Sweden in 2000

Prototype beta-blocker

Potential alternative to warfarin

Angina

Alteplase

Fibrinolytic

Acute MI

Dabigatran

Thrombin inhibitor

Atrial fibrillation

Dobutamine

Beta-1 agonist

HF

Mexiletine

Anti-arrhythmic (Cl.1)

Arrhythmias

Tenectaplase

Thrombolytic

MI

Borg

Disopyramide

Antiarrhythmic (Cl.1)

Arrhythmias

BMS

Pravastatin

Statin

Atherosclerosis & MI

Omapatrilat

ACE + NE inhibitor

Angina & HF

Captopril

ACE Inhibitor

CHF & post-MI

Celltech

Phase of development

Irbesartan

A II receptor blocker

HF

Procainamide

Antiarrhythmic (Cl.1)

Arrhythmias

Cholestyramine

Bile acid trapper

High cholesterol & lipid levels

Labetalol

Alpha/beta blocker

Angina coupled with high blood pressure

Digitoxin

Heart stimulant

HF

Centocor

Abciximab

Monoclonal antibody

MI

Chugai

BO-653

Anti-oxidant

Atherosclerosis

Forest

Nisoldipine

Ca antagonist (Cl.2)

Angina

GlaxoSmithKline

Digoxin

Cardiac glycoside

Chronic HF & arrhythmias

Piboserod

5HT4 antagonist

Arrhythmias

480848

Lp-PLA2 inhibitor

Atherosclerosis

501516

PPAR inhibitor

Hyperlipidaemia

590735

PPAR inhibitor

Hyperlipidaemia

Goldshield

Warfarin

Anti-coagulant

Atrial fibrillation

Lilly

Abciximab

Antiplatelet MAb

MI, UA

Fasidopril

ACE inhibitor

HF

3M Healthcare

Flecainide

Anti-arrhythmic (Cl.1)

Arrhythmias

Merck Pharma

Nicotinic acid

Vitamin

High cholesterol

Merk Sharp & Dohme

Tirofiban

Antiplatelet

UA and some forms of MI

Simvastatin

Statin

Atherosclerosis

Losartan

A II receptor blocker

HF with stroke risk

Ezetimibe

Cholesterol absorption inhibitor

Atherosclerosis

With Sanofi Aventis

In patients scheduled for or undergoing angioplasty


Product

Product

Target

Company

name/number

type

disease

Napp

Aminophylline

Xanthine

HF

Theophylline

Xanthine

HF

Diltiazem

Ca antagonist (Cl.3)

Angina

Novartis

Pfizer/Pharmacia

Procter & Gamble

Roche

Fluvastatin

Statin

Atherosclerosis

Valsartan

A II receptor blocker

Hypertension & post MI

Metoprolol

Beta blocker

Hypertension, angina & arrhythmias

Acipimox

Nicotinic acid type

High cholesterol

Amlodipine

Ca antagonist (Cl.2)

Ischaemia & angina

Atorvastatin

Statin

Hypercholesterolaemia

Colistipol

Bile acid trapper

High cholesterol and fats levels

CP-529,414

CEPT inhibitor

Atherosclerosis

Dalteparin

LMWH

UA and some forms of MI

Eplerenone

SARA

HF

Phenytoin

Anti-arrhythmic (Cl.1)

Arrhythmias

Prazosin

Selective alpha-1 blocker

HF

Spironolactone

K-sparing diuretic

HF

Azimilide

K channel blocker

Arrhythmias

Pexelizumab

Anti-C5 monoclonal antibody

MI

Reteplase

Fibrinolytic

Acute MI

Carvedilol

Alpha/beta blocker

HF & angina

Sankyo Pharma

Pitavastatin

Statin

Hyperlipidaemia

Sanofi Aventis

Clopidogrel

Antiplatelet

MI

Milrinone

PDE inhibitor

HF

SR121463

Vasopressin receptor blocker

HF

Irbesartan

A II receptor blocker

HF

Amiodarone

Anti-arrhythmic (Cl.3)

Arrhythmias

Adenosine

Purine nucleoside

Arrhythmias

Dronedarone

Anti-arrhythmic (Cl.3)

Arrhythmias

SR149744

Ani-arrhythmic

Arrhythmias

Enoxaparin

LMWH

UA and some forms of MI

Nicorandil

K channel activator

Angina

Schering Plough

Eptifibatide

Antiplatelet (gIIb/IIIa blocker)

UA and MI

Servier

Ivabradine

Antiarrhythmic & SAN blocker

Angina

Solvay Healthcare

Tedisamil

K channel blocker

Arrhythmias HF

Daglutril (SLV306)

ECE & NE inhibitor

Omacor

Unsaturated fatty acids Post-MI arrhythmia

Sovereign

Hydralazine

Vasodilator

HF

Takeda

Caldaret (MCC-135)

Ca uptake enhancer and Na/Ca exchange system inhibitor

HF & MI

Candesarten (TCV-116)

A II receptor blocker

HF

Wyeth

Acetazolamide

Carbonic anhydrase inhibitor

HF

Yamanouchi

Nicardipine

Ca antagonist (Cl.2)

Stable angina

Conivaptan (YM087)

AV1 and AV2 receptor antagonist

HF

Phase of development PC

I

2 3

L

Comments

Also available from Trinity, Elan, Galen, Genus, Merck & Sanofi-Aventis

Also in development by Lilly

Phase 3 in high risk angina patients. Also from BMS

With BMS

Follow-up to dronedarone

Possible use also in HF

Approved for hypertension in 1997

PC, 1,2,3 = Preclinical and Phase 1, 2, and 3 clinical trials; L = Licensed/Authorised; A II = Angiotensin II; ACAT = Acyl CoA cholesterol acyl transferase; AV = Arginine-vasopressin; C5 = Complement C5; Ca = Calcium; CA = Carbonic anhydrase; CETP = Cholesteryl Ester Transfer Protein; CS = cardioselective; ECE = Endothelin Converting Enzyme; HF = Heart failure (chronic or congestive); 5HT = 5-hydroxy tryptamine; IL = Interleukin; K+ = Potassium; LMWH = Low Molecular Weight Heparin; Lp-LPA2 = Lipoprotein-Associated Phospholipase A2; MAb = Monoclonal antibody; MI = myocardial infarction; Na = Sodium; NCS = Non-cardioselective; NE = Neutral endopeptidase; PDE = Phosphodiesterase; PPAR = Peroxisome Proliferator Activated Receptor; SARA = Selective Aldosterone Receptor Antagonist; TNFa = Tumour Necrosis Factor-alpha; UA = Unstable angina.


SOME USEFUL ADDRESSES

There are many charities in the field of heart disease, some large and others small. The larger ones make a major contribution to research as well as providing patient support. Smaller charities provide valuable information about specific areas of heart disease and offer more targeted help and guidance to people and their families, including booklets, leaflets, newsletters, and confidential advice. It would be impossible to list them all here.

Copies of this booklet and others in the Target series are also available from the ABPI: Alzheimer’s, Cancer, Crohn’s & Colitis, Depression, Diabetes, Epilepsy, Leukaemia, Migraine, Osteoporosis, Pain, Parkinson’s, Prostate, Rheumatoid Arthritis, Schizophrenia, Skin, Stroke.

Heartsforlife have a very valuable web site which can be found at www.heartsforlife.co.uk

www.abpi.org.uk

BRITISH CARDIAC PATIENTS ASSOCIATION 2 Station Road Swavesey Cambridgeshire CB4 5QJ Helpline 01223 846 845 Telephone 0800 479 2800 Email enquiries@bcpa.org.uk Web site www.bcpa.co.uk

ANTICOAGULATION EUROPE P O Box 405 Bromley BR2 9WP Telephone 020 8269 6875 Email anticoagulationeurope@ntlworld.com Web site www.anticoagulationeurope.org

They are also available on our web site:

BRITISH HEART FOUNDATION 14 Fitzhardinge Street London W1H 6DH Helpline 08450 70 80 70 Administration 020 7935 0185 Web site www.bhf.org.uk

BRITISH HEART FOUNDATION SCOTLAND Ground Floor 4 Shore Place Edinburgh EH6 6UU Telephone 0131 555 5891 Email scotland@bhf.org.uk

BRITISH HEART FOUNDATION WALES 21 Cathedral Road Cardiff CF11 9HA Helpline 0870 600 6566

HEART UK 7 North Road Maidenhead Berkshire SL6 1PE Telephone 01628 628 638 Email ask@heartuk.org.uk Web site www.heartuk.org.uk

CHEST HEART AND STROKE SCOTLAND 65 North Castle Street Edinburgh EH2 3LT Telephone 0131 225 6963 Email admin@chss.org.uk

CARDIOMYOPATHY ASSOCIATION 40 The Metro Centre Tolpits Lane Watford Hertfordshire WD18 9SB Telephone 01923 249 977 Web site: www.cardiomyopathy.org

The information contained in Target Heart Disease was assembled during 2004. While every effort has been made to ensure the accuracy of the information contained in Target Heart Disease, the complexity of pharmaceutical research means that not all potential medicines listed here will successfully complete their clinical trials. Readers should therefore note that their availability for eventual use is by no means certain. The author and the ABPI disclaim all responsibility for errors and omissions. Printed by BSC Print, London, Designed by Ann Henderson

Target heart disease  
Target heart disease  
Advertisement