Over little more than a generation coronary artery disease has become the major cause of death in Western industrialized societies. In Britain it accounts for one in three deaths in men and one in four deaths in women; unskilled men aged 20 to 64 years have twice the risk of professional people. In the United States over 500000 deaths annually are attributed to coronary disease. The accuracy of morbidity statistics is less reliable, but information from The British Regional Heart Study, obtained by means of an administered questionnaire and ECG recordings in middle-aged men drawn at random from medical practices in 24 British towns, showed that about 8 per cent of individuals had angina and 15 per cent had definite or possible ECG evidence of ischaemic heart disease. The burden placed on the community in terms of this morbidity with its attendant economic and health care costs is enormous: in Britain coronary heart disease is estimated to be responsible for 12 per cent of all working days lost due to illness and the cost of treatment is over £500m per year.

Epidemiological studies have shown a marked difference in death rates due to coronary disease between and within countries. This might be explained by environmental or genetic factors but as individuals who migrate tend to acquire the risk characteristics of their new locality, these differences seem to be related to lifestyle and exposure to risk factors rather than to genetic susceptibility.

Another phenomenon that has become apparent since the 1960s is the decline in death rates from coronary disease in the United States and some other countries. In America this amounts to a reduction of 53 per cent amongst people aged 35 to 74 years and is most evident in the white population, in the more affluent, and in younger age groups. Theoretically this reduction could be due to a fall in the incidence of the disease, to improved medical care, or to both. The management of acute myocardial infarction in particular has certainly improved over this time, with some reduction in case fatality rates, but the main benefit is more likely to be associated with an increased awareness within the population of the need to avoid coronary risk factors.

The Framingham study identified three major risk factors: elevated serum cholesterol levels, high blood pressure, and cigarette smoking. Any one doubles the risk of coronary heart disease but the presence of all three increases the risk by more than eight times.

Cholesterol is necessary for the maintenance of cell membranes, production of bile salts, and synthesis of steroids; triglycerides are used mainly as an energy supply. Both are transported in the plasma as complexes (lipoproteins) that can be classified according to their density. Low density lipoprotein (LDL) is the major cholesterol-carrying component of plasma and the main determinant of coronary risk. High density liprotein (HDL) plays a role in the removal of cholesterol from cells and its transport to the liver and has an inverse relationship to coronary risk; it may be protective, at least in subjects with elevated LDL levels.

A number of genetically inherited conditions result in elevation of the LDL component of cholesterol. The best known of these is familial hypercholesterolaemia, in which there is a deficiency or virtual absence of LDL receptors—liver cells being the main source. The heterozygous form of the disorder affects about 1 in 500 of the population: these individuals lack 50 per cent of receptors, and have serum cholesterol levels of 8 to 13 mmol/l. In the rare homozygous form cholesterol levels may reach over 20 mmol/l; affected individuals suffer from accelerated atherosclerosis in the aortic root and coronary tree, which may lead to a requirement for coronary and valve surgery in the first two decades of life and even to a need for heart and liver transplantation. However the most common cause of elevated LDL cholesterol is not one of the single gene defects but a condition in which LDL synthesis is increased and its rate of catabolism decreased.

Renal disease, hypothyroidism, liver disease, alcoholism, dysproteinaemia, and steroid treatment may all be secondary causes of hyperlipidaemia.

One of the first longitudinal prospective studies was the Seven Countries Study, which examined and followed up men aged 40 to 59 years from countries with very different coronary death rates. It demonstrated the close relationship between serum cholesterol levels and the risk of developing coronary disease and also showed that blood cholesterol values were related to the intake of dietary saturated fat. Although smoking and hypertension were identified as major risk factors, these were found to have little effect in populations with low serum cholesterol levels. Further support for the association of cholesterol and coronary disease has come from the Multiple Risk Factor Intervention Trial (MRFIT), in which data from more than 350000 men showed a continuous relationship between cholesterol levels and death rates from coronary disease (Fig. 1) 1752. Smokers with the highest systolic blood pressure and cholesterol levels had coronary heart disease death rates about 20 times greater than non-smokers with the lowest systolic blood pressure and cholesterol levels.

Trials involving dietary change, with or without the administration of lipid-lowering drugs, have consistently shown that the incidence of non-fatal myocardial infarction and mortality due to coronary disease is reduced by interventions which lower cholesterol levels. There is a reduction in coronary deaths of about 2.5 per cent for every 1 per cent reduction in serum cholesterol level.

However a significant fall in overall mortality has not been demonstrated. An analysis of pooled data from six primary prevention trials showed that over a mean period of 5 years the intervention groups suffered 28 per 100000 fewer deaths from coronary disease and 29 per 100000 excess deaths from suicide, homicide, and accidents. This apparent increase in violent death is unexplained but has led some to question the wisdom of widespread cholesterol reduction, except for those with the highest levels and those exposed to other risk factors. Nevertheless the beneficial effect on non-fatal myocardial infarction alone makes cholesterol-lowering treatment worthwhile and cost effective.

There is also evidence to suggest that secondary prevention is beneficial. Patients who already have clinical coronary disease face a far greater risk of fatal and non-fatal infarcts than those without overt disease; this risk can be reduced by lowering elevated cholesterol levels. Furthermore a fall in LDL and an increase in HDL cholesterol is associated with serial angiographic evidence of less progression and even some regression of coronary lesions.

Hypertension is recognized as an independent risk factor for stroke, cardiac failure, and coronary artery events, but whereas intervention trials have clearly shown a reduction in the incidence of stroke and cardiac failure with lowering of blood pressure, this is not true of coronary disease. The Hypertension Detection and Follow-up Program in the United States enrolled male and female patients, including a large group with diastolic blood pressures between 90 and 104 mmHg, and randomized half to standard care from their family doctors and half to what was called ‘stepped care’, which involved increasing drug treatment in order to achieve a satisfactory reduction in blood pressure. This study and the Australian Therapeutic Trial, which used a placebo control in following patients with diastolic pressures between 95 and 109 mmHg, both showed a significant reduction in mortality in the stepped care group compared to controls. This reduction was associated with lower diastolic pressures but did not include a reduction in death rate from myocardial infarction. This finding has been attributed, without proof, to a detrimental effect of antihypertensive drug treatment on blood fats and serum potassium, although another possible reason is that trials lasting for only a few years may not show an effect on an atheromatous process which builds up over decades.

The Multiple Risk Factor Intervention Trial showed that for a given level of cholesterol, cigarette smoking increased coronary death rates. Cigarette smoking has a number of potentially hazardous effects, including activation of the sympathetic nervous system with enhanced platelet reactivity, and a carbon monoxide-induced fall in the oxygen carrying capacity of the blood. Women over the age of 35 years who take the contraceptive pill and smoke are at an increased risk of having a myocardial infarction; post-infarct patients are twice as likely to have another heart attack if they continue to smoke. However the effect of cigarette smoking is largely one of increasing the risk in subjects made susceptible by other risk factors, especially elevated cholesterol levels.

To some extent these are associated with the major risk factors already described, and clustering of risk factors in an individual or a group is common. Obesity is easily recognized as a clinical manifestation of the coronary prone individual; however, its very proper reputation as a risk factor is largely due to its association with hypertension, diabetes, and elevated cholesterol levels. Obesity has not been clearly defined as an independent risk factor. Diabetes is often associated with obesity, elevated cholesterol levels, and hypertension; in some African and Asian countries where this association is not found, diabetes is then not recognized as an independent risk factor. A family history of premature coronary disease is often, although not solely, related to environmental factors such as a diet rich in saturated fats, smoking, and familial hypercholesterolaemia. Having a first-degree relative with clinical coronary disease in their 50s confers a significant risk. Females are at lower risk than males, at least up to the time of the menopause. This may be related to a higher level of HDL cholesterol in women, but the difference has become less marked, possibly because of an increase in the prevalence of smoking among younger women.

The role of triglycerides as a separate risk factor is controversial, but an elevated level may be associated with other lipid abnormalities and other risk factors. For example a high triglyceride level is often found in diabetics and in those with a low level of HDL cholesterol.

Vigorous and habitual exercise leads to a fall in blood pressure and a rise in HDL cholesterol; this was shown to reduce the risk of cardiac events in American college graduates who retained an active lifestyle compared to more sedentary contemporaries. Further support for the protective effect of exercise comes from a large British study in middle-aged civil servants followed for a mean period of 9 years. This showed that, to be effective as a means of reducing the risk of fatal and non-fatal myocardial infarction, exercise has to be at least moderately intense and current; a past history of vigorous exercise is not protective. Older men entered at the age of 55 to 64 years also benefited, and required less vigorous exercise.

LDL cholesterol is taken up by cells with LDL receptors. Excess cholesterol is removed from interstitial tissues by the lymphatics and from cells by HDL cholesterol. However the arterial intima, which has to absorb LDL particles directly through the endothelial layer, has no lymphatic drainage; the concentration of LDL cholesterol is therefore considerably greater in the intima than in most other tissues. LDL particles not taken up by intimal cells appear to be modified and oxidized forming aggregates which are engulfed by macrophages; these then transform into foam cells. Accumulations of foam cells can be seen macroscopically even in the first decade of life, and are known as fatty streaks.

The further development of the atheromatous plaque is determined by a series of complex interactions between lipoprotein molecules, platelets, smooth muscle cells, and malfunctioning endothelial cells. The combination of a high level of circulating LDL cholesterol and endothelial injury, possibly invoked by a number of factors such as hypertension or smoking or simply as a result of a distorted pattern of blood flow, may increase the flow of LDL particles into the intima, overwhelming the foam cells. These die, releasing their cholesterol core. Other modified LDL particles accumulate in the deeper intimal layer as lipid droplets, which eventually coalesce into the lipid pool of the mature atheromatous plaque.

Platelets also play a role as they become aggregated and deposited on areas of endothelial damage, leading to release of vasoconstrictive and growth factors which promote the build up of smooth muscle cells and collagen. Some plaques are predominantly fibrous, and others lipid laden. The end result is often a plaque that contains a lipid pool in the depths of the intima bordered by smooth muscle cells and foam cells and covered by a fibrous tissue cap (Fig. 2) 1753.

The characteristics of the plaque may be important in determining the nature of the patient's symptoms and the risk of an acute ischaemic event. Pathological studies have shown that plaques may be eccentric or concentric, and may have a large cholesterol pool or may be largely fibrotic. In arteries with eccentric plaques, part of the wall circumference is healthy: this may be prone to vasospastic and dynamic change which can cause intermittent narrowing of the lumen accompanied by angina which is not consistently related to effort. The concentric plaque is likely to be rigid with a fixed luminal narrowing; this gives a more consistent pattern of symptoms related to an increase in myocardial oxygen demand.

In the majority of cases unstable angina and myocardial infarction are triggered by disruption of the fibrous cap. This is most likely to occur at the edge of the cap at its junction with the relatively healthy wall and in plaques that have a large unsupported lipid core. If the split is superficial, thrombosis may follow platelet aggregation and release of vasoconstrictive factors. This creates a subtotal occlusion of the artery and the clinical features of unstable angina. However, if there is deep exposure of collagen and the lipid-rich pool, thrombus formation, initially within the intima but extending into the lumen, is more likely to cause total occlusion and myocardial infarction.

Coronary angioscopy in individuals with unstable angina has shown in life what pathologists have demonstrated at autopsy: a ruptured plaque with superimposed non-occlusive thrombus. The latter may show evidence of having been formed at different times. Each deposit may be related to periods of pain and with microinfarcts in the distal coronary bed, suggesting embolization. Knowledge of these arterial changes has made cardiologists aware of an arteriographic correlation with irregular undercut lesions and filling defects due to thrombus commonly seen during arteriography in unstable angina patients.

Angiographic studies show that the stenosis present before plaque rupture occurs need not be severe; this explains why asymptomatic and active subjects can quite suddenly experience unstable angina, myocardial infarction, or sudden arrhythmic death. Other studies in patients with coronary disease who have died of non-cardiac causes show that plaque fissuring may be quite common, and only a minority may be associated with thrombotic occlusion. The fibrous cap can heal with or without spontaneous lysis of thrombus; the amount of intimal thrombus incorporated into the new plaque structure determines whether the resulting stenosis is unchanged or worse.

The resting 12 lead ECG may be entirely normal in patients with widespread coronary disease. Minor abnormalities must be interpreted in the light of the patient's history: ST segment depression and T wave flattening or inversion are consistent with ischaemia but also occur in those with hypertensive heart disease, those receiving digoxin treatment and during hyperventilation. Pathological Q-waves on the ECG record is firm evidence of coronary disease as long as a cardiomyopathy can be excluded.

ST segment depression recorded fortuitously during pain confirms the diagnosis of coronary disease; ST segment elevation implies severe proximal stenosis of a coronary artery, perhaps with superimposed spasm, isolated spasm, which is uncommon, or an evolving myocardial infarction.

During infarction the ECG usually shows the classical changes of ST segment elevation in the distribution of the infarct, deep T wave inversion, and loss of R wave height with progression to Q-waves. Cardiac arrhythmias such as sinus bradycardia, ventricular ectopics, and idioventricular rhythm are common. The initial ECG is occasionally normal, but serial records will show change, and extending the lead system to V7–8 may show infarct changes in the posterolateral territory. Patients with inferior wall infarcts should have right ventricular leads recorded, looking for evidence of right ventricular infarction. Patients who do not develop Q-waves tend to have smaller infarcts.

Ambulatory ECG monitoring has an obvious role to play in detecting cardiac arrhythmias but may also be used to detect ST segment shifts in patients thought to have vasospastic angina or episodes of silent ischaemia.

This allows the likelihood of coronary disease to be determined, functional capacity to be determined and prognosis to be estimated. It is of fundamental importance in the management of patients presenting with anginal chest pain and after myocardial infarction.

Several ECG changes are considered to be indicative of exercise-induced ischaemia. The most common is depression of the ST segment by at least 1 mm (0.1 mV) 80 ms after the J point (this is the junction of the QRS complex and ST segment). Horizontal or down-sloping ST depression is more specific for coronary disease than is up-sloping (Fig 3) 1754. ST segment elevation usually occurs over an area of myocardial damage associated with akinesia or aneurysm formation, but it represents induced ischaemia in the absence of Q-waves.

Other findings which relate to myocardial ischaemia also have to be taken into consideration. These include the level of exercise achieved, the systolic blood pressure response, the heart rate and workload at the onset of ischaemic changes, and symptoms of chest pain, breathlessness, and faintness.

Exercise-induced ST depression can occur in hypertensive patients without angiographic evidence of coronary disease and in those with mitral valve prolapse. Digitalis preparations may exaggerate ST segment changes and antianginal drugs such as &bgr;-blockers and calcium antagonists may restrain cardiac work sufficiently to mask ischaemic changes which otherwise would be evident at a low workload.

The prevalence of coronary disease increases substantially as the history of chest pain becomes more typical of angina, and in men more than women. There is therefore no diagnostic advantage in performing exercise tests in men with classical angina. The same is true of women with non-specific chest pain, in whom the likelihood of coronary disease is very low and the predictive value of a positive exercise test is only 10 per cent. Table 2 504 shows the predictive value of positive and negative exercise tests in patients with different clinical presentations, but should be used only as a guide. For diagnostic purposes exercise testing is best restricted to women with typical angina and patients with atypical angina. Women in the latter category with a positive result may need to undergo additional tests such as an exercise thallium study in order to assess more accurately the post-test risk of having coronary disease. Patients with marked ECG abnormalities early in the exercise period are more likely to have coronary disease.

The prognosis of patients with coronary disease is determined largely by left ventricular function and the severity of coronary disease. Patients who develop marked ST segment depression of 2 mm or more at a low level of exercise (unable to complete Stage 2 of the Bruce protocol) or at a low heart rate have almost a 90 per cent chance of having multivessel or left mainstem coronary disease, and hence a greater risk of early death. Loss of the normal blood pressure rise with exercise also places the patient in a high-risk group, especially if this is accompanied by ECG and clinical signs of severe ischaemia. Follow-up studies of patients with three-vessel coronary disease and normal or mildly impaired left ventricular function show that survival is related to the level of exercise achieved. The 4-year mortality rate is 47 per cent in those unable to complete level 1 of the Bruce protocol (Fig 4) 1755. In any one patient most prognostic information can be assembled from knowledge of left ventricular function, obtained by clinical examination or otherwise, the peak exercise level attained, and the response of the ST segment.

Echocardiography can be applied serially at the bedside, and has many uses in patients with presumed coronary artery disease: the dimensions and function of heart chambers can be studied, regional wall motion abnormalities due to ischaemia can be detected at an early stage, and complications of myocardial infarction such as ruptured ventricular septum and acute mitral reflux can be identified. It also helps in the recognition of transient myocardial ischaemia: carried out before, if possible during, and again immediately after stress testing it can show induced regional wall motion abnormalities. Exercise stress or intravenous pharmacological agents (which allow better image quality) such as dobutamine, dipyridamole, or adenosine are used.

Although complementing standard exercise testing, radionuclide imaging techniques fall short of providing entirely accurate data about the extent and the functional significance of coronary stenoses. Also there is an unmet clinical need to identify viable but non-contractile myocardium due to chronic ischaemia (‘hibernating’ myocardium). For this, positron emission tomography using tracers which relate to the metabolic activity of the myocardium and to myocardial perfusion is best but not readily available. The most common indications for radionuclide imaging are a low likelihood of coronary disease on clinical evaluation but a positive exercise test, a high pretest likelihood of coronary disease but a negative exercise test, a resting ECG which is unsuitable as a marker of ischaemia (for example digitalis effect, left bundle branch block and pre-excitation), and inability to exercise.

Thallium-201 is a radioactive tracer which is avidly taken up by myocardial cells: its distribution is related to viability of these cells and myocardial perfusion. It is injected at peak exercise and shortly afterwards a two-dimensional or preferably tomographic picture is obtained using a gamma-camera. A further imaging 3 to 4 h later allows comparison. Defects which disappear with time are considered to represent ischaemic but viable myocardium, while persistent defects indicate irreversible damage, or at least severe myocardial ‘stunning’ (Fig. 5) 1756. A second thallium-201 injection given under resting conditions may improve the ability to distinguish between myocardial scarring and ischaemia.

Similar representation of myocardial perfusion can be achieved without exercise by injecting thallium-201 shortly after the intravenous injection of dipyridamole, which causes dilation of coronary arterioles. Redistribution of thallium uptake then defines areas of comparatively poor perfusion. This is obviously useful in patients who are unable to exercise. Intravenous infusion of adenosine has also been used as a coronary vasodilator, its use to some extent limited by minor side-effects, particularly chest discomfort, headache, and flushing.

Thallium-201 imaging is more sensitive and specific than standard exercise testing for the diagnosis of coronary disease but is considerably more expensive. However, when applied to selected patient groups it extends the evidence for or against the presence of coronary disease and determines the need for coronary arteriography. Detection of multiple or large perfusion defects indicates a high risk of cardiac morbidity and mortality.

Another radionuclide technique involves imaging of left ventricular global and regional wall motion at rest and during supine exercise. Intravenous technetium-99m is used to label the blood pool and exercise-induced ischaemia is detected by its effect on left ventricular ejection fraction and regional wall motion. Patients with coronary disease whose ejection fraction falls with exercise have a higher incidence of cardiac events. Intravenous dobutamine can be used as a stress agent in those patients unable to exercise. In practice, radionuclide angiography is often used to gauge the functional relevance of known coronary disease and to justify an intervention on prognostic grounds.

Coronary arteriography is usually combined with pressure measurement in the left ventricle, and single or biplane left ventriculography. Performed percutaneously from the femoral artery or through a brachial arteriotomy under local anaesthesia, it defines the distribution and severity of coronary disease, collateral flow patterns, and the postoperative patency of saphenous vein and internal mammary arterial grafts.

The risk of the procedure is related to a number of variables, particularly the clinical state of the patient: there is an increased risk of serious complications in those with angina at rest or pulmonary oedema and in those with severe left mainstem disease. In patients studied electively at one large British centre emergency surgical revascularization was necessary in 0.24 per cent of patients undergoing coronary arteriography. Overall mortality should not exceed 0.1 to 0.2 per cent. Although accepted as the final arbiter of coronary disease, even experienced observers tend to underestimate the severity of lesions that appear to show a diameter stenosis of less than 60 per cent. This problem can be reduced considerably by the use of edge-enhancing quantitative computer analysis of angiograms.

Coronary arteriography is rarely performed because of the need to know whether or not a patient has coronary disease. Exceptions are those whose occupation may depend on the result, such as airline pilots. The main indications are firstly to assess patients with limiting or unstable angina for surgical or angioplasty treatment, secondly to evaluate more accurately the prognostic relevance of positive non-invasive tests, and thirdly to identify further jeopardized myocardium after myocardial infarction. Guidelines for coronary arteriography have been published.

Stable angina is a sensation of discomfort, often aching, gripping, or crushing in character, which may be felt anywhere from the lower jaw to the epigastrium, including the arms and upper back, and is related to effort and emotional upset and eased by rest. In some cases the limiting factor is less clear and the patient may have difficulty in describing it other than as a feeling of vague unease. Some patients may have ‘breakthrough angina’ with typical discomfort disappearing as the patient warms up and in others dyspnoea may be an anginal equivalent. The probability of an individual patient having coronary disease increases as the history becomes more typical of angina and with the unmasking of risk factors.

Examination may also provide supportive evidence of coronary disease, although patients presenting with angina are often normal in this regard. Nevertheless one should seek evidence of lipid deposition such as tendon xanthomata, peripheral vascular disease, and hypertension. Auscultation of the heart usually reveals a prominent fourth heart sound and patients with previous myocardial damage may have features of cardiac failure.

Medical management aims to relieve symptoms and improve effort tolerance by means of drug treatment, to identify high risk subjects so that treatment designed to improve survival can be given, and to advise on and treat risk factors in the expectation that progression of the disease will be slowed.

&bgr;-Blocking drugs are the mainstay of treatment. They act by reducing heart rate, cardiac contractility, and blood pressure, and thus myocardial oxygen consumption. They therefore redress the imbalance between demand and supply which causes ischaemia. They extend the duration of angina-free exercise and reduce the frequency and severity of asymptomatic ischaemia detected by ambulatory ECG monitoring. Side-effects consist mainly of loss of vigour and cold sensitivity. Contraindications are heart failure, sinus node disease, atrioventricular heart block, and asthma.

Calcium antagonist drugs include those with a predominant myocardial action such as verapamil and others like nifedipine which have a largely peripheral effect. Verapamil and diltiazem are effective antianginal drugs when used singly, but nifedipine is best prescribed with a &bgr;-blocker or diltiazem. The latter combination is associated with an increased incidence of side-effects in the form of ankle oedema, flushing, and headaches. All calcium antagonist drugs can exacerbate cardiac failure.

A nitrate drug should be tried in virtually all patients with angina and, if tolerated, continued in one of its many forms. The increased use of long acting-preparations has uncovered the phenomenon of nitrate tolerance. In practical terms tolerance is likely to occur after 24 h of chronic exposure: preparations should therefore be prescribed to cover the period of maximum stress but also to give adequate drug-free intervals. Aspirin has been shown to reduce the risk of myocardial infarction in patients with stable angina.

In stable chronic angina the severity of discomfort bears little relationship to the severity of underlying coronary disease. As risk can be assessed by exercise testing the logical conclusion is that virtually everyone with such a diagnosis should undergo a standard exercise test or radionuclide study. This may not be practical, and if selection is necessary one should refer patients with a recent history of angina, those who have a reduced exercise capacity compared to others of their age, and those with a worsening pattern of angina. Some of the last patients may have unstable angina, in which case exercise testing is inappropriate.

Those whose symptoms are not adequately controlled by medication or who are at high risk of cardiac events, as determined by exercise testing should undergo coronary arteriography and assessment for coronary angioplasty or surgery.

This occupies an intermediate position between stable angina and myocardial infarction, with a 10 to 15 per cent risk of progressing to myocardial infarction or sudden death. It can be defined as angina occurring with minimal effort and at rest but without a rise in cardiac enzymes more than twice the upper limit of normal. These patients may have pathological evidence of plaque fissuring and non-occlusive thrombus, and specialist advice and hospital care are essential.

Clinical management consists of antithrombotic treatment, administration of antianginal drugs, and often early coronary arteriography. Angioplasty or surgery may be required in high-risk patients, such as those with recurring episodes of pain at rest with ECG changes despite 24 h of adequate medical treatment; those with haemodynamic deterioration (e.g. left ventricular failure or hypotension during bouts of pain), and those with evidence of persistent ischaemic ECG changes in the absence of pain. Patients without these features should initially receive medical treatment, followed by coronary arteriography if angina occurs during ward activity or if a predischarge exercise test is positive.

Medical treatment of unstable angina reduces the risk of infarction and improves survival. Trials of aspirin treatment showed a 40 per cent reduction in non-fatal myocardial infarction and death (Fig. 6) 1757. Intravenous heparin has a similar beneficial effect, although it is not clear whether it confers additional protection to patients already taking aspirin. &bgr;-Blockers reduce the risk of recurrent chest pain and early infarction but nifedipine does not, and it may even be detrimental unless given in conjunction with a &bgr;-blocker.

Patients with unstable angina should be admitted to a coronary care unit, given aspirin and, in the absence of contraindication to such therapy, given a &bgr;-blocking drug such as metoprolol or atenolol along with oral nitrates. Nifedipine can be added for patients already receiving &bgr;-blockers. Further pain should be treated by intravenous heparin and by substituting intravenous nitrate for the oral preparation. Heparin should be administered for at least 48 h after the last bout of chest pain and aspirin treatment should be long-term. This regimen will relieve symptoms in the majority of patients with unstable angina. If not, coronary arteriography should be carried out. Patients who deteriorate haemodynamically may be placed at less risk if coronary arteriography is performed after insertion of an intra-aortic balloon pump.

The patient presenting early with a myocardial infarction usually has severe chest pain and appears anxious and frightened. Sweating and vomiting are common. Other physical signs are determined largely by vagal activity and by the size of the evolving infarct, but a wide area of impulse activity over the precordium is often found in patients with anterior wall infarction and a raised jugular venous pressure in patients with right ventricular infarction. There may be a third heart sound, and a fourth is almost always present. Within 24 h a pericardial friction rub may be audible.

The ECG usually confirms the diagnosis; a chest radiograph may show evidence of pulmonary congestion and echocardiography can be very useful in confirming the presence of a wall motion abnormality early in the course of the illness, especially if the ECG is unhelpful.

Elevation of cardiac enzyme levels is essential for the diagnosis, and most laboratories will measure the cardiac isoenzyme of creatine kinase (MB-CK) and the less specific aspartate transaminase (AST) and one or other of the lactic dehydrogenase isoenzymes (LDH) so that a profile of enzyme release, with early MB-CK, intermediate AST and late LDH peaking can be built up. The size of the infarct can be judged from the total release of cardiac enzymes.

Several drugs relieve myocardial ischaemia and improve survival of patients with myocardial infarction. A meta-analysis of pooled trials has suggested that intravenous nitrates reduce mortality if given early to patients with moderate to large infarcts. * 6 Care should be taken, however, to avoid nitrate-induced hypotension, as this may lead to infarct extension. Nitrates should not be used if there is a suspicion of hypovolaemia.

When given intravenously, &bgr;-blockers can rapidly relieve the pain of infarction in selected patients with tachycardia and elevated blood pressure, and their role in improving prognosis has been proved by a number of trials.

The greatest impact in terms of reducing mortality from infarction has followed the introduction of thrombolytic drugs. About 80 per cent of patients with Q-wave infarcts studied by arteriography within 4 h show thrombotic occlusion of the relevant coronary artery. Large-scale trials have shown that thrombolytic drugs given intravenously or by intracoronary injection, can result in reperfusion in a high proportion of patients, with improved long-term survival. In most centres it is not practical to provide routine intracoronary treatment and the intravenous route has become the standard. The three thrombolytic preparations used most commonly are streptokinase, recombinant tissue plasminogen activator, and anisoylated plasminogen-streptokinase activator complex (anistreplase). Analysis of trial results clearly shows that coronary patency rates 90 min after intravenous administration of tissue plasminogen activator are greater than those after administration of streptokinase (70 per cent versus 55 per cent). Large scale comparative trials have shown no difference in clinical outcome and survival: streptokinase and tissue plasminogen activator given within 6 h of onset lead to a similar 25 per cent reduction in early mortality, which is maintained for at least a year. However, a preliminary report of another large trial establishes a survival benefit over streptokinase from a more rapid than usual infusion of tissue plasminogen activator, given under 4 h. * 7 Although survival benefit is most marked in those treated early, benefit is seen in patients given streptokinase up to 24 h after onset of symptoms and for all age groups.

One of the more dramatic findings came from the Second International Study of Infarct Survival trial (ISIS–2) which showed that in patients with suspected acute myocardial infarction aspirin given alone is associated with a 23 per cent reduction in 5-week mortality; when combined with streptokinase mortality falls by 42 per cent at 5 weeks (Fig. 7) 1758. ISIS–3 compared the use of streptokinase, tissue plasminogen activator, and anistreplase in patients admitted within 24 h of suspected myocardial infarction. There was no difference in mortality at 35 days but both tissue plasminogen activator and antistreplase were associated with an increased risk of stroke when compared to streptokinase. The place of heparin, given after thrombolysis, is unresolved; there may be a reduction in coronary reocclusion rates but at the expense of more bleeding complications.

Despite a sense of urgency imposed by the wish to start thrombolytic treatment early, great care has to be taken to exclude patients in whom thrombolysis could have catastrophic consequences, for example those with aortic dissection or bleeding from a peptic ulcer. The main contraindications are shown in Table 3 505. Because of the risk of an allergic reaction and because antibodies to streptokinase may persist for at least a year and render it ineffective when given in the usual dose, tissue plasminogen activator should be given to patients with a history of prior exposure to streptokinase or anistreplase.

The main complication of these drugs is an increased incidence of bleeding. Comparable rates of bleeding (3 to 4 per cent) have been found with all the preparations used although major bleeds—those requiring transfusion—and intracranial bleeds occur in less than 1 per cent.

Patients seen within 24 h of onset of possible myocardial infarction should be transferred to hospital without delay and assessed immediately by medical staff. Oxygen and morphine are given, and as soon as myocardial infarction is suspected aspirin 300 mg is prescribed. In the absence of contraindications, thrombolytic treatment is started. If there is likely to be an unavoidable delay in getting the patient to hospital then with a confident diagnosis, prehospital thrombolysis using anistreplase has been shown to be effective. The decision to initiate thrombolytic treatment more than 12 h after the onset of pain should be influenced by factors such as site of infarction (anterior wall infarcts have a higher risk of death than those in the inferior wall), persistent pain, ST segment elevation, and the presence of residual R waves on the ECG. Streptokinase has been the first choice: it is relatively cheap, most trials show it to be as effective as the other preparations, and it is less likely to cause a stroke. If the patient is tachycardic, with a well-maintained blood pressure and without evidence of cardiac failure or other contraindications, atenolol (intravenous, and then oral) should be prescribed and continued long term unless the patient falls into a low risk category (as defined by exercise testing) or is intolerant of the drug.

The patient can leave the coronary care unit 24 to 36 h after admission. Gentle mobilization starts at about 48 h, with discharge at about 7 days. The exact timing of these events varies depending on the extent of myocardial damage. A predischarge exercise test should be performed in patients who have had thrombolytic treatment and for those who had a small enzyme rise or non-Q-wave infarct. In the former, there is the possibility of successful reperfusion and a severe residual coronary stenosis; the latter because they are often thought to have had an incomplete infarct. Patients who develop symptoms or ECG evidence of ischaemia or who show a poor exercise capacity during a submaximal test should undergo coronary arteriography. Otherwise this is not required.

For those with a satisfactory pre-discharge exercise test there is little to be gained from a symptom limited test at 3 weeks, although the latter is an alternative means of assessment for many with uncomplicated infarcts. Those who complete stage three of the Bruce protocol without ischaemic changes have a 1-year predicted mortality rate of less than 2 per cent.

After acute myocardial infarction changes occur in the myocardium; these comprise early thinning of the infarcted area and then over months dilatation of the left ventricle which may, in time, result in clinical heart failure. Studies have shown a reduction in the incidence of cardiac failure and mortality when angiotensin converting enzyme inhibitors were given to patients with asymptomatic left ventricular dysfunction recovering from myocardial infarction. While benefit was shown for those started late in their hospital course this was not true with early administration. Aspirin has been shown to reduce reinfarction rate and should be continued long term if tolerated.

Antiarrhythmic treatment may be necessary early in the course of infarction. Ventricular fibrillation or fast ventricular tachycardia usually responds to 200 J defibrillation, and if it occurs shortly after the onset of infarction prophylactic antiarrhythmic drug treatment is not required. Intravenous lignocaine (lidocaine) is given for bouts of ventricular tachycardia, or for ventricular ectopics of increasing frequency, especially when closely coupled (R on T) or in runs. (Overall the randomized trial data show no evidence of benefit from intravenous magnesium.) Temporary pacing may be required for complete heart block, asystole, or symptomatic bradycardia not responding to atropine. If thrombolytic treatment is given venous access for pacing should be via a compressible site.

In the majority of patients with large anteroapical infarcts, echocardiography shows left ventricular thrombus; this makes them liable to systemic embolism, which is most likely to result in a stroke. Prophylactic anticoagulation may reduce this risk: heparin should be administered initially and warfarin treatment then continued for 6 months.

Echocardiography with Doppler is also reliable for the diagnoses of rupture of the intraventricular septum, rupture of the free wall of the left ventricle with pseudoaneurysm formation, and papillary muscle dysfunction or rupture leading to acute mitral reflux. All should be considered for early surgical repair.

Once a patient has reached hospital the most common cause of death is severe pump failure. When faced with a patient in cardiogenic shock the initial approach may be to measure right heart and pulmonary wedge pressures along with cardiac output estimations. Only by these means can one entirely exclude underfilling of the left ventricle resulting from diuresis or fluid restriction particularly if there is right ventricular infarction, when a high filling pressure is required to maintain output. Fluid replacement and inotropic and vasopressor drugs can be administered to maintain an optimum left ventricular filling pressure of about 18 mmHg whilst maintaining arterial pressure and cardiac output. However, in the absence of obvious hypovolaemia this thorough approach should be subordinate to the urgent need to reperfuse ischaemic myocardium and the best practical solution is often to take the patient to the catheterization laboratory where both the haemodynamic and occlusive coronary abnormalities can be identified and corrected. There is evidence that the survival rate of about 10 per cent for patients in cardiogenic shock may be improved by emergency coronary angioplasty with or without thrombolysis: one retrospective study reported an early survival rate of 50 per cent.

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