The term ‘coronary’ was first conceived to describe a crown-like arrangement of the arterial blood vessels supplying the heart muscle. If the heart is considered as an upside-down cone with the flat base placed at the level of the atrioventricular groove, then the coronary arteries may be visualized as a ring at the base of the cone with branches which pass towards the tip (Fig. 5.1). This network of coronary arteries arises from two main origins in adjacent aortic sinuses. The anterosuperior sinus gives rise to the right coronary artery (RCA). This passes down the anterior atrioventricular (AV) groove. It gives rise to marginal branches which supply the anterior free wall of the right ventricle (RV). At the junction between the anterior and inferior aspects of the RV it gives off a significant branch—the acute marginal artery. It then passes inferiorly and in 70% of subjects terminates in a right posterior descending branch which supplies the inferior aspects of the RV, left ventricle (LV) and interventricular septum.

Fig. 5.1 Major coronary arterial blood vessels.

The posterior aortic sinus gives rise to the left coronary artery stem which quickly branches into the left circumflex artery. This mirrors the right coronary artery in the posterior AV groove and likewise gives off marginal branches. The other branch is the left anterior descending (LAD) artery which passes down the anterior interventricular groove to the apex and turns on to the posterior surface where it passes in the posterior interventricular groove for a variable distance. During this course the LAD gives off diagonal and septal perforating branches which supply the anteroseptal, anterolateral and apical portions of the left ventricle and the anterior papillary muscle.

The left circumflex artery gives off marginal branches, the obtuse marginal artery being a dominant feature. It passes inferiorly and usually terminates. In some individuals it turns to form a left posterior descending artery which follows the interventricular groove to a watershed with the distal portion of the LAD.

The precise arrangement of branches is variable. In about 70% of individuals the right coronary is dominant and its posterolateral and right posterior descending branches supply the inferior interventricular septum, left ventricular free wall and posterior papillary muscle. In 20% of individuals the left circumflex artery is dominant and gives rise to a left posterior descending artery and supplies the inferior portion of the heart. In 10% neither is dominant and the supply is shared.

The sinoatrial node is supplied by a branch of the RCA in 60% of cases and from the circumflex artery in 40%. The AV node is supplied by the RCA in 90% of cases. Damage to vessels supplying portions of the conducting system may lead to specific defects. In the case of damage to the sinus nodal artery it may lead to ‘sick sinus syndrome’ in which the frequency of generation of cardiac action potentials becomes randomly variable and inappropriate (tachy-brady syndrome). Damage to the supply to the AV node or bundle of His may lead to complete heart block (see Chapter 3) and is particularly associated with inferior myocardial infarction.

Though the arteries cross the surface of the heart, because they pass in the atrioventricular and interventricular grooves they clearly delineate the main chambers of the heart. The majority of the venous drainage is via a system of veins which run against the arterial system back to vessels which drain round the atrioventricular groove. Passing posteriorly is the great cardiac vein and passing anteriorly is the small cardiac vein, both of which drain into the coronary sinus. The coronary sinus passes under the floor of the left atrium and into the right atrium. The anterior cardiac veins drain directly to the right ventricle and atrium. The remainder of the venous drainage is in the tiny Thebesian veins which also connect mainly to the right atrium and right ventricle.

An imbalance between the oxygen demands of the heart and amount that can be supplied by the coronary blood supply leads to the development of an hypoxic pain originating in the heart which is called angina (see p. 55). An outline of a clinical case history is shown in Case 5.1:1.

Case 5.1 Blood supply to the heart: 1

Development of chest pain with exercise

Colin Davies is a 50-year-old smoker. Over the last 3 months he has noticed that he has became more short of breath than usual when walking to the local shops. He has a sensation of pressure and tightness in his chest. More recently he found that when he walks up the stairs in his house he gets a dull, aching pain which feels to come from the left side of his chest and extends down his left arm.

Colin saw his GP who suspected angina pectoris and arranged for him to have an exercise test at the local hospital. After 4 minutes on the treadmill Colin was feeling short of breath and had developed pain in his chest. The ECG showed ST segment depression in the lateral chest leads (V₄–V₆). The test was terminated at 4½ minutes when Colin felt he could not go on. His pain disappeared after 1 minute of rest and this was accompanied by the resolution of the ST segment changes on his ECG.

Colin’s blood pressure was normal and his GP checked his fasting blood lipids and glucose which were also normal. The GP strongly recommended that he stop smoking. In view of Colin’s symptoms and exercise test results his GP commenced him on oral glyceryl trinitrate (GTN) spray. He explained that this was to be used whenever Colin had chest pain symptoms.

This case history raises the following questions:

1. Why does angina pain occur and why does it get worse with exercise?

2. What is meant by ST segment depression and what does this change in the ECG suggest?

3. Why did the GP check Colin’s blood pressure and fasting plasma lipids and glucose?

4. How do nitrate drugs such as GTN help to relieve angina?

Aspects of the answers to these questions are to be found in the text of this chapter. ECG changes are discussed in Chapter 7.

Interesting facts

Under resting conditions, the heart muscle extracts about 75% of all the oxygen which arrives in the coronary arteries. A substantial increase in oxygen delivery can only be provided by an increase in coronary blood flow not by further extraction of oxygen from haemoglobin. The corollary of this is that disease-related limitation of coronary blood flow impairs cardiac performance and leads to cardiac pain (angina).

Regulation of coronary blood flow

At rest the myocardium receives about 5% of cardiac output. In the normal ‘textbook’ person there is a potential for cardiac output to increase about fivefold during exercise (see Chapter 13). This is roughly paralleled by changes in coronary blood flow and the necessity for this is largely dictated by the high oxygen extraction rate of cardiac muscle.

In skeletal muscle, under resting conditions, only of the order of 25–30% of the oxygen carried in arterial blood is extracted for use in the muscle (Fig. 5.2). The saturation of haemoglobin with oxygen in skeletal muscle therefore decreases from about 97–98% (arterial blood) to about 70% (venous blood). Even under resting conditions the venous drainage from cardiac muscle is only 25% saturated, meaning that of the order of 75% of the oxygen in arterial blood has been extracted and used metabolically. During exercise, increased oxygen delivery to contracting skeletal muscle can be provided by a combination of increased blood flow (see Chapter 13) but also by increased (up to 80–90%) extraction of oxygen from haemoglobin. In the heart as oxygen extraction at rest is already about 75% there is limited scope for increasing oxygen delivery by this route. Studies with ¹¹C-acetate positron emission tomography (PET) scanning suggest that, in the heart, oxygen extraction from arterial blood can rise to 90% during exercise but even this is a limited way of increasing oxygen delivery. The bottom line is that if the heart needs increased oxygen supply it must be mainly provided by increased coronary blood flow. The corollary of this is that pathological mechanisms which impair coronary blood flow must limit cardiac performance.

Fig. 5.2 Oxygen–haemoglobin dissociation curve. Extraction of oxygen from arterial blood in skeletal muscle is typically 25–30%. Oxygen extraction by cardiac muscle even under resting conditions is 75%.

Coronary blood flow, particularly to the left ventricle, is particularly affected by the contraction of the myocardium which crushes coronary vessels (Fig. 5.3). This mainly affects blood vessels in the subendocardial layers of the heart muscle and the blood vessels on or close to the surface of the heart are relatively unaffected. The subendocardial layers are therefore more prone to ischaemic damage. In the left ventricle, because of the high pressures developed in the contracting ventricle, coronary blood flow is much higher during diastole than during systole. In the right side of the heart intraventricular pressures are lower and so the effect of ventricular systole on coronary blood flow is less marked. When heart rate increases during exercise the duration of diastole is shortened more markedly than the duration of systole. This imposes a limitation on increases in coronary blood flow and is probably the limiting factor on maximum exercise ability in normal individuals.

Fig. 5.3 Right and left coronary blood flow correlated with ventricular pressure.

Coronary blood flow is autoregulated (Fig. 5.4). This means that over a range of mean arterial pressures, probably in humans from about 50 to 120 mm Hg, coronary blood flow is relatively independent of arterial pressure. This is thought to result especially from responses of arterioles which are less than 150 μm diameter. Thus, as the arterial pressure increases through the autoregulatory range the smooth muscle in the wall of these arterioles contracts to maintain flow constant.

Fig. 5.4 Autoregulation of coronary blood flow.

‘Myogenic’ effects on vascular smooth muscle mean that stretch of smooth muscle results in contraction. It is a mechanism that was first described by Bayliss in 1902 and is probably the dominant mechanism providing autoregulation of coronary flow. There are complex interactions between various blood vessel microdomains and possibly also with non-myogenic components which provide the overall autoregulatory response.

The major regulatory factor determining coronary blood flow is myocardial oxygen demand coupled to the production of vasodilator metabolites. These metabolites particularly affect blood vessels in the 150–170 μm size range. The vascular smooth muscle is thought to be particularly sensitive to changes in [adenosine], [K⁺], [H⁺] and to local changes leading to an increase in interstitial osmolarity (see Chapter 9). A major part of this vasodilator action is mediated by the opening of ATP-sensitive K⁺ channels. This leads to hyperpolarization and consequently to relaxation of the smooth muscle.

The source of the vasodilator adenosine has been a subject of conjecture. Berne (1980) proposed that it was produced under hypoxic conditions by the complete dephosphorylation of ATP. An alternative pathway was put forward by Deussen (1989), in which adenosine was formed from ATP via the intermediate formation of S-adenosyl methionine and S-adenosyl homocysteine. Both pathways are thought to contribute to interstitial [adenosine]. The following points seem to be relevant to understanding these events. ATP, ADP and AMP are all polar molecules as a result of ionization of their phosphate groups and will not easily cross cell membranes. Adenosine is non-polar and can leave the myocardial cell once it has been formed. Adenosine in the interstitium has a very short half-life (of the order of 10 s) and so must be continuously generated. [ATP] inside cells is about 5 mmol/L but interstitial [adenosine] is about 10 nmol/L, a 500 000-fold difference in concentration. Therefore, only a very small proportion of the intracellular ATP would need to be metabolized to provide relatively big changes in interstitial [adenosine] (Fig. 5.5).

Fig. 5.5 Regulation of coronary vascular smooth muscle contraction by the metabolite adenosine and by the endothelial cell-derived mediator nitric oxide (NO).

Endothelial influences on blood vessel diameter are described elsewhere (see Chapter 9). Increased shear stress on the endothelium leads to production of nitric oxide and thence to vasodilatation. This occurs particularly in large coronary arteries but it does not appear to contribute to the mechanism of autoregulation. Endothelial dysfunction leading to impaired nitric oxide release is a characteristic of a number of pathological conditions which will affect the coronary blood vessels including hypercholesterolaemia, atherosclerosis and hypertension. Assessment, prevention and treatment of endothelial dysfunction is emerging as an important area of clinical medicine, especially in relation to the coronary circulation.

Modulation of coronary blood flow via the sympathetic nervous system primarily acts through α₁-adrenoceptors on relatively large vessels. Vessels less than 100 μm diameter predominantly have α₂-adrenoceptors but α₁-receptors are also present. Activation of either of these populations of α-receptors leads to vasoconstriction and this is the dominant sympathetically mediated response. In the past there has sometimes been confusion about the role of β-receptor-mediated vasodilatation. Although such receptors do exist in limited numbers on coronary vessels, the vasodilator response which follows β-agonist infusion is mainly a result of increased metabolite (e.g. adenosine) generation following an increased force of ventricular muscle contraction (i.e. an inotropic response). Coronary vasodilatation directly as a result of β-adrenoceptor activation is a very minor component of coronary vascular control.

The role played by cardiac sympathetic nerves in relation to coronary blood flow is still controversial. During exercise the effects of sympathetic vasoconstrictor nerves are overwhelmed by the effects of vasodilator metabolites. However, α-receptor-mediated coronary vasoconstriction may, in some circumstances, contribute to the genesis of the ischaemic pain angina.

Ischaemic heart disease

Ischaemic heart disease is the most common cause of death in the Western world. It may occur either because the coronary blood supply is reduced or because the oxygen demand of the heart has increased for instance as a result of hypertrophy. The regions of the heart most at risk are the subendocardial layers, the region most affected by vascular compression during systole.

The most frequent cause of obstruction in a main coronary artery is atherosclerosis. As this is not confined to the coronary circuit but may develop in any major vessels in the high-pressure arterial side of the circulation the details of the pathogenesis of atherosclerotic lesions are described in Chapter 8.

Occlusion of the coronary arteries may become critical in various ways:

• Progressive narrowing of vessels by atheromatous plaques.

• The plaque and the associated reduction in blood flow velocity may provide a focus for thrombus formation with consequent further reduction in blood flow. The possibility also exists of embolization of the thrombus.

• With time, a plaque becomes a rigid structure but is still surrounded by pliable blood vessel wall. There is therefore a risk of rupture (fissuring) of the plaque which provides another site for thrombus formation. The processes involved in thrombus formation are described below.

Thrombosis

Thrombosis is best considered as the inappropriate activation of the blood clotting system in a living vessel (with flowing blood) resulting in a thrombus forming inside the vessel. The thrombus may either suddenly or slowly occlude the lumen of the vessel leading to blood flow problems distal to the blockage.

A thrombus is therefore a solid mass, composed of blood constituents, which develops in a living vessel, including the heart. It is vitally important to realize that a thrombus can only form during life—this is in contrast to a clot which can occur after death or in blood taken from the circulation and put in a test tube. Thus although the key proteins and cells in thrombosis are the same as those in the clotting cascade, thrombosis is usually considered a pathological rather than a physiological process. However, this is simplistic. In reality, tiny thrombi probably form in the circulation all the time, particularly where there are small areas of trauma to the endothelium. These microthrombi are quickly removed once the endothelial defect has healed. Classically, there are three main predisposing factors, known as ‘Virchow’s triad’, which favour the formation of a thrombus:

• changes in the intimal surface of the vessel

• changes in the pattern of blood flow

• changes in the blood constituents.

Damage to the endothelium is an important factor in thrombosis as it exposes collagen in the intima and media of the vessel wall. This will trigger platelet adhesion as a prelude to thrombus formation. Endothelial damage can be caused by atherosclerosis, trauma, inflammation, substances in cigarette smoke and hypertension, amongst others.

Change in blood flow is also an important factor. Slow flow, as occurs with incompetent venous valves and dilated veins, can lead to pooling of blood. On the arterial side of the circulation turbulent blood flow near atherosclerotic plaques or aneurysms can lead to damage to the endothelium (see Chapter 8). Both scenarios will lead to increased platelet–vessel wall interaction.

A change in blood constituents is another important factor in thrombus formation. Significant increases in total red cell or platelet numbers, as seen in polycythaemia, thrombocythaemia and leukaemia, can predispose a patient to thrombosis. Congenital deficiencies of natural anticoagulants such as protein S and protein C may also lead to thrombus formation.

Essentially, in thrombosis, the natural antithrombogenic processes in the body are overwhelmed by prothrombogenic factors. Thus, if there is damage to the endothelium, there is exposure of subendothelial collagen. By a receptor-mediated process, platelets stick to the collagen and to Von Willebrand factor found in the subintimal matrix. The platelet mass forms an aggregate, then ADP and prostaglandin A₂ are released which encourages more platelet aggregation. The platelets can bind fibrinogen causing a cellular plug to form.

The use of mechanical methods (e.g. compression stockings) and the drugs heparin, warfarin and aspirin which contribute to antithrombotic therapy are discussed later in this chapter.

As soon as the platelet plug has formed, fibrinolytic systems are activated which prevent propagation of the thrombus (Fig. 5.6). However, the presence of one or more of Virchow’s triad will tip the scale towards thrombus formation.

Fig. 5.6 Fibrinolytic pathway showing the sites of action of thrombolytic drugs.

Thrombi can form in any part of the cardiovascular system and to some extent the appearance of the thrombus depends on:

• the calibre of the vessel

• the speed of blood flow.

A thrombus forming in a small-sized vessel may cut off the blood supply. This is called an occlusive thrombus. In a large vessel such as the aorta or heart, the thrombus may be restricted to the wall only, a mural thrombus. This is much less likely to cause problems with occlusion of the vessel it has formed in, but may lead to emboli which can block subsequent smaller vessels. In a medium-sized vessel, there may be significant restriction of blood flow as a result of mural thrombus.

The speed of blood flow influences the composition of a thrombus. Thus, in very fast-flowing arterial blood, thrombi tend to be mainly composed of platelets and fibrin and therefore appear pale and laminated, whereas in slow-flowing blood in veins the thrombus is rich in red blood cells and looks more gelatinous.

Once a thrombus has formed, a number of ‘events’ may occur:

• lysis/dissolution

• propagation

• organization/recanalization

• embolization.

Lysis/dissolution

The fibrinolytic systems (Fig. 5.6) remove the thrombus and the vessel returns to normal.

Table 5.1

Types of embolus and their characteristics

Embolic material	Characteristics
Thrombus (90% of major emboli)	Venous thrombosis usually from deep veins of legs (95% of cases) becomes pulmonary embolus
	Thrombus forming over an atheromatous plaque or myocardial infarct or in a fibrillating atrium can give rise to systemic embolus. This leads to infarction, e.g. brain, kidneys, gut and limbs
Atheromatous plaque debris	Frequent cause of problems in lower limbs
Infective emboli	Particularly from vegetations on heart valves produced by infective endocarditis
Fat	Generated during long bone trauma and in severe burns. Emboli travel to lungs, brain and kidney particularly
Gas	May occur during surgery (air embolus) or during rapid decompression of divers (nitrogen)
Amniotic fluid	Occurs via damaged uterine blood vessels at childbirth
Tumour tissue	Route for tumour metastasis
Foreign bodies	Small amounts of material produce a granulomatous reaction where they lodge. At-risk patients include intravenous drug users

Anti-thrombotic therapy

In hospitalized patients the methods used to try to avoid the formation of thrombus depend on the risk involved. For moderate-risk patients mechanical methods such as elasticated stockings can be used. For higher-risk patients this may be supplemented with low-dose heparin. This is a sulphated mucopolysaccharide (glycosaminoglycan) molecule derived commercially from pig intestinal mucosa or the lungs of cattle. It forms a complex with the clotting cascade protein antithrombin which results in the activation of antithrombin. Thrombin promotes the last stage of the clotting mechanism, conversion of fibrinogen to fibrin (Fig. 5.6). Heparin also inhibits several other stages in the clotting cascade. It is inactive given orally and so must be administered by the intravenous or subcutaneous routes.

The anticoagulant warfarin is orally available. Its main activity is preventing the formation of the active form of vitamin K and thus suppressing the synthesis in the liver of factors II (prothrombin), VII, IX and X which are all part of the clotting cascade. Factor VII is the most sensitive to vitamin K deficiency. Warfarin is the most widely used oral anticoagulant but it has a narrow therapeutic index and therefore its effects must be regularly monitored.

A further step in thrombus formation, the aggregation of platelets, is inhibited by aspirin. This non-steroidal anti-inflammatory drug (NSAID) blocks cyclooxygenase (COX) pathways. Aspirin is 150 times more effective at blocking the constitutive COX-1 pathway than the inducible COX-2 pathway. The result is a decrease in prostaglandin and thromboxane production. Effects on platelet aggregation are mediated at very low aspirin dose levels by a reduction in thromboxane A₂ (TXA₂) synthesis by platelets. Prophylactic use of low-dose aspirin to decrease the risk of thrombosis has become widespread.

Thrombolytic therapy

There are a number of thrombolytic drugs available but the most commonly used are streptokinase and genetically engineered recombinant tissue plasminogen activator (rt-PA). All of the drugs activate plasminogen to form plasmin, an enzyme which promotes the breakdown of fibrin and fibrinogen into degradation products (Fig. 5.6). This leads to lysis of a thrombus and may result in some restoration of blood flow. How effective thrombolytic therapy is depends on factors such as the age of thrombus and the access of the drug to the thrombus.

The thrombolytic drugs are given intravenously or intra-arterially and have been shown in clinical trials to reduce the mortality rate after a myocardial infarction. The greatest benefits are achieved if thrombolytic therapy is commenced within 70 minutes of the onset of pain. There are a number of contraindications which must be seriously evaluated. These include a previous history of cerebrovascular events (stroke), a recent gastrointestinal bleed or a recent operation; in short, any situation where there is a risk of haemorrhage. A fall in blood pressure (hypotension) associated with release of the vasodilator bradykinin may occur with drugs such as streptokinase.

After thrombolysis with rt-PA heparin must be given intravenously for 48 hours to reduce the likelihood of re-occlusion of the vessel. This is not necessary with streptokinase as it has a longer duration of action.

Angina

Angina is pain which arises from areas of cardiac muscle which are underperfused and lack adequate supplies of oxygen. Typically it is a central, crushing chest pain, of variable severity. Classically it radiates to the left arm or into the neck. Its key feature is that it occurs on exertion and is relieved with rest. In some individuals the pain may be less apparent and the sensation is more of chest tightness and breathlessness (dyspnoea). Relief of the pain by the use of short-acting nitrates such as sublingual glyceryl trinitrate (GTN) (see below) is considered a useful diagnostic feature.

The hypoxia results from a discrepancy between demand for myocardial oxygen and maximum coronary blood flow capacity (Fig. 5.7). The key difference between angina and myocardial infarction is that with angina the myocardial hypoperfusion is reversible and does not cause permanent myocardial damage. A theory is that the pain is elicited by the interstitial accumulation of adenosine which activates unmyelinated nerve fibres. This is based on the observation that angina pain can be mimicked in normal individuals in a dose-related way by coronary artery infusion of adenosine. The lack of associated ECG changes shows that actual hypoxia is not occurring as a result of the adenosine infusion.

Fig. 5.7 Key factors determining the balance between the workload of the heart and oxygen delivery to cardiac muscle.

‘Unstable angina’ occurs at rest. It is presumably brought about by coronary vasospasm at resting levels of demand and may be difficult to distinguish from infarction, though the pain of infarction is usually more severe and prolonged. ECG changes will reflect myocardial ischaemia, i.e. ST segment depression rather than the elevation associated with infarction (see Chapter 7). Treatment should be supportive using vasodilators and anticoagulants in order to prevent progression to full infarction.

Myocardial hypoxia is also produced by an inadequacy of oxygen transport. Anaemia reduces the oxygen-carrying capacity of the blood whilst the presence of cyanosis means that the available haemoglobin is inadequately oxygenated. Both these factors may generate tissue hypoxia and angina in a borderline coronary insufficiency state.

Factors which disproportionately increase the workload of the myocardium, such as aortic stenosis or hypertension, may also precipitate angina in a patient whose coronary arteries might otherwise be adequate. The hypertensive patient may suffer a ‘double whammy’, increased tendency to develop atherosclerosis and an increased afterload imposing a workload on the heart which necessitates extra oxygen delivery.

Interesting facts

Viagra (sildenafil) was initially developed as a potential drug for the treatment of angina. The well known uses in erectile dysfunction became apparent from side effect reports when the drug was introduced into clinical trials.

Drugs used in the management of angina

Strategies for the treatment of angina can be targeted at either increasing the coronary blood flow or decreasing the work done by the heart. In the latter case oxygen demand is decreased. This can be achieved by reducing the force of cardiac muscle contraction either by reducing preload on the heart or by reducing cardiac contractility (see Chapter 4). Other changes in workload of the heart can be achieved by reducing heart rate or arterial blood pressure (decreased afterload).

Four major classes of drugs are used:

• organic nitrates

• β-adrenoceptor blockers

• calcium channel blockers

• potassium channel openers.

The organic nitrates are exogenous sources of the natural vasodilator nitric oxide (see Chapter 9). The most widely used drug in this category is glyceryl trinitrate (GTN). There is an increasing number of other drugs including isosorbide dinitrate and isosorbide mononitrate. A major site of action of organic nitrates is on the venous capacitance vessels. Relaxing smooth muscle here leads to a reduced preload on the heart and thus reduces cardiac output (see Chapter 4). Vasodilatation on the arterial side of the circulation, particularly in this case of large arteries, leads to a reduction in blood pressure and reduced afterload on the heart. Effects of nitrates on coronary blood vessels are often minimal. Vessels may already be maximally dilated under the influence of local metabolites (Chapter 9) which have accumulated in the hypoxic cardiac tissue. Nitrates may help to improve flow through collateral vessels and also relieve coronary artery spasm when that is a cause of angina.

As many nitrate drugs undergo extensive first-pass metabolism in the liver they are not suitable for absorption in the main part of the gastrointestinal tract. Sublingual (under the tongue), buccal (between upper lip and gum) or transdermal (through the skin from an adhesive patch) routes are commonly used sites of administration.

β-adrenoceptor blockers (beta-blockers) reduce the force of cardiac contraction (reduce contractility) and lower blood pressure (reduce afterload) (see Chapter 4). These effects reduce oxygen demand by the heart and limit exercise performance. There is also a reduction in heart rate and, with the consequent lengthening of diastole, the phase of the cardiac cycle when most of the coronary perfusion occurs is prolonged. Some β-adrenoceptor blockers, such as atenolol, are referred to as ‘cardioselective’ as they are relatively selective for the β₁-subtype of receptors, the main type found in the heart. The first β-adrenoceptor blocker developed, propranolol, is non-selective and has approximately equivalent actions on β₁ and β₂ receptors. This drug is still widely used but is contraindicated in asthmatics as the β₂ blockade may lead to bronchospasm.

Case 5.1 Blood supply to the heart: 2

Limitations of Colin’s drug therapy

Colin, whose presenting symptoms were described in Case 5.1:1, did find that the GTN relieved his symptoms. However although he gave up smoking he still found that he was using the GTN more and more frequently. He sought further advice from his GP who prescribed a long-acting oral nitrate drug. Colin’s angina symptoms initially improved and he found walking to the shops and back much easier. Unfortunately, subsequently, his symptoms worsened and he sought further advice from his GP who prescribed atenolol 50 mg od. However Colin found the atenolol had too many side effects and so, after 2 weeks, he stopped taking the beta-blocker. He described the problems of the drug to his GP as a feeling of continuous fatigue and an inability to concentrate. This was made worse by a disturbed sleep pattern with vivid dreams and hallucinations.

This case history raises the following questions:

1. Why might Colin’s angina be getting worse with the passage of time?

2. What was the rationale for prescribing the beta-blocker atenolol?

Aspects of the answers to these questions are to be found in the text of this chapter.

Calcium channel blockers such as nifedipine, amlodipine, verapamil and diltiazem reduce the flux of Ca⁺⁺ ions into smooth muscle and cardiac muscle but not skeletal muscle. All of the calcium used to trigger skeletal muscle contraction is stored within the sarcoplasmic reticulum inside the muscle cells.

The main site of action of calcium channel blockers is on voltage-gated L-type (long-acting) slow Ca⁺⁺ channels. Voltage-gated T-type (transient) channels are also blocked in pacemaker tissue of the sinoatrial and atrioventricular nodes (see Chapter 4). Beneficial effects of calcium channel blockers in the relief of angina include systemic arteriolar vasodilatation (reduced arterial blood pressure and thus reduced afterload), coronary artery dilatation (in the case of vasospasm), a reduction in heart rate and reduced cardiac contractility (reduced workload). It should be stressed that the different drugs in this broad category have a wide spectrum of activity and they are not identical. For example, verapamil and diltiazem both reduce heart rate but the dihydropyridine drugs nifedipine and amlodipine do not. Amlodipine also does not significantly reduce cardiac contractility but, like nifedipine, it has marked effects leading to arteriolar vasodilatation.

Potassium channel opening drugs such as nicorandil open ATP-sensitive K⁺ channels and hence lead to smooth muscle hyperpolarization. This inhibits the opening of L-type voltage-gated Ca⁺⁺ channels and so produces vasodilatation in both systemic and, where possible, coronary blood vessels.

Myocardial infarction

Myocardial infarction (MI) results when there is complete interruption of blood flow to an area of myocardium. It involves necrosis of cardiac muscle followed by inflammatory cell infiltration and, because cardiac myocytes cannot regenerate, eventual fibrous repair. The subendocardial tissue in the left ventricle, which as described earlier is most prone to ischaemia, is most at risk. Figure 5.8 shows an infarcted area of tissue. The classical model for infarction is rupture of an atherosclerotic plaque (see Chapter 8) with thrombosis (see p. 53) and vasospasm completely occluding the lumen of a critical blood vessel. Frequently this is one of the major epicardial blood vessels described at the start of this chapter and shown in Figure 5.1. The infarction occurs downstream from the occluded blood vessel. As already noted, there is considerable variation in the anatomy and distribution of the main coronary arteries. However, some generalizations can be made regarding common sites of obstruction.

Fig. 5.8 Infarcted area of tissue. Myocardial infarct (I) in the lateral wall of the left ventricle. Source: Stevens A, Lowe J 2000.

• Left anterior descending artery obstruction accounts for about 50% of cases. It produces infarcts in the anterior wall of the left ventricle with characteristic ECG changes in the anterior chest leads (V₁–V₃). Occlusion of this artery is sometimes a cause of sudden death.

• Right coronary artery obstruction occurs in about 30% of cases and leads to inferior wall infarction and sometimes posterior septum infarcts. The ECG changes are seen in leads II, III and aVF.

• Circumflex artery obstruction occurs in about 20% of cases and leads to lateral wall infarction with ECG changes in leads I, aVL and the lateral chest leads (V₄–V₆).

Depending on the vessel, the volume of muscle it supplies and the underlying structures, infarction may vary from being a mild warning sign for the individual to a terminal event. Structures which are of particular importance are the papillary muscles, the left ventricular myocardium and the conducting system. For example, rupture of a papillary muscle may result in severe mitral valve regurgitation which greatly reduces the effectiveness of an already compromised left ventricle. Infarcts can also lead to the development of arrhythmias which may be life threatening.

Interesting facts

New York Heart Association Functional Classification

This grading applies to patients with angina or heart failure:

Class I No limitations during ordinary activity

Class II Slight limitation during ordinary activity, e.g. mild or occasional angina or dyspnoea

Class III Marked limitation of normal activities without symptoms at rest

Class IV Unable to undertake physical activity without symptoms; symptoms may be present at rest.

Investigation of myocardial infarction

The clinical picture associated with MI is variable. A frequent symptom is severe crushing chest pain (angina) which may have a sudden onset or may build up more slowly. Accompanying symptoms often include nausea, vomiting and sweating. Patients may give a history of angina or non-specific chest discomfort over previous weeks but in at least 10% of patients, particularly the elderly, MI is painless.

MI is typically identified with characteristic ECG changes and increases in the serum level of proteins released from the disrupted myocardial cells. In the past plasma or serum measurements of total creatine kinase (CK), aspartate aminotransferase (also known as serum glutamic oxaloacetic transaminase, SGOT) and total lactate dehydrogenase (LDH) have been used as indicators of cardiac necrosis. However these enzymes are widely distributed in the body and lack specificity to cardiac tissue. More recently the use of other markers has increased. The MB isoenzyme of CK is found in the heart and levels in blood do not start to rise until 4 hours after infarction. CK-MB levels fall again within 72 hours. The CK-MB test is frequently used to provide early confirmation of a diagnosis of MI. The more specific markers troponins T and I are now the gold standard for myocardial cell necrosis as these structural proteins are found solely in myocardial cells. Their physiological function is in the coupling of a rise in intracellular [Ca⁺⁺] to cross-bridge formation as part of the contraction of cardiac muscle (see Chapter 2). Troponin T and I levels may be modestly raised following the cardiac hypoxia associated with unstable angina. After an acute MI troponin levels are increased within 3–6 hours, reach a peak within 14–20 hours and return to normal after 5–7 days.

Case 5.1 Blood supply to the heart: 3

Colin’s heart attack

Eight months later Colin was woken at 3.00 a.m. by a severe, central, crushing chest pain. It was as bad as any pain he had ever experienced. He felt cold and was sweating profusely. His wife called an ambulance and he was taken into the local hospital. A 12-lead ECG showed ST elevation in the lateral leads associated with T wave inversion. The casualty officer gave him a dose of aspirin and intravenous morphine. After review by the medical registrar Colin was moved to the coronary care unit where streptokinase was administered. Six hours from the onset of the pain blood samples were sent for measurement of cardiac enzymes. The results showed a substantial rise in creatine kinase (CK-MB) strongly supporting the clinical diagnosis of acute myocardial infarction. Following thrombolysis Colin was treated with heparin in order to maintain arterial patency. Further blood tests showed elevated levels of troponin T during the subsequent 15-hour period. The troponin T levels had returned to normal 10 days later.

After recovery from his infarction the patency of Colin’s coronary vasculature was investigated by angiography. He was subsequently treated by coronary artery bypass grafting and made an uneventful recovery. Currently his exercise tolerance has improved considerably and he is free of angina pain.

This case history raises the following questions:

1. What is the basis for the use of the drugs aspirin and morphine?

2. What are the beneficial effects of streptokinase and when ideally should it be given?

3. What is the value of measurements of creatine kinase and troponin T? Why is the time course of blood sampling for these tests important?

Aspects of the answers to these questions are to be found in the text of this chapter.

Since thrombosis appears to be an important component of the process of infarction the use of thrombolytic therapy, e.g. streptokinase or recombinant tissue-plasminogen activators such as alteplase or reteplase, has become a central component of care in suspected MI. These compounds, rather than being simply anticoagulant, positively promote activation of the fibrinolytic system thereby helping to break down the clot (see p. 54).