Clinical manifestations of atherosclerosis

Over a lifetime many plaques may develop in a given patient, the great majority of which will remain clinically unnoticed. Clinical disease is usually provoked by only one out of many plaques, and ranges in severity from relatively benign symptoms to life-threatening diseases. The more serious conditions often follow acute changes in the plaques.

Plaque morphology and the vulnerable plaque concept

Autopsy studies on large series of patients who died from myocardial infarction have shown that the atherosclerotic plaques that develop a plaque rupture and subsequent thrombus have distinct morphological features. This has led to the recognition of so-called vulnerable plaques: plaques with a high risk of developing thrombotic complications (Fig. 13.7). Typically vulnerable plaques have a thin fibrous cap, a large lipid core and prominent inflammation. It is thought that pronounced inflammatory activity contributes to degradation and weakening of the plaque that increases the risk of rupture. Secretion of proteolytic enzymes, cytokines and reactive oxygen species by the plaque inflammatory cells orchestrates this process. On the other hand, the plaques that gradually progress to highly stenotic lesions (as, for example, in stable angina pectoris) often have a large fibrocalcific component with little inflammatory activity.

Fig. 13.7 Coronary artery thrombosis. An atheromatous plaque has ruptured. There is haemorrhage within the lesion and thrombosis of the lumen.

Secondary prevention of atherosclerotic complications

There is good evidence from many different trials that treatment with cholesterol-lowering drugs reduces cardiac events both in patients with a history of coronary heart disease and in asymptomatic subjects with hypercholesterolaemia. At present ‘statins’ are the most widely used compounds. They act as specific inhibitors of HMG CoA reductase, an enzyme that has a rate-limiting action in hepatic cholesterol synthesis. Besides their cholesterol-lowering effect, they probably reduce inflammation within atheromatous lesions and promote plaque stability (conversion of a lipid-rich inflamed plaque into a fibrous plaque).

Another approach is to minimise the risk of thrombus formation on established atheromatous lesions. The earliest changes in thrombus formation include platelet activation following interaction with thrombogenic plaque components. Low doses of aspirin, which inhibits aggregation of platelets, are given to many patients with clinical evidence of atheromatous disease and have undoubted beneficial effects. The United Kingdom National Service Framework for Coronary Heart Disease also recommends that patients with established coronary heart disease should receive beta-blockers and angiotensin converting enzyme inhibitors or angiotensin receptor antagonists.

Surgical and percutaneous interventions

Several invasive techniques have been developed to reduce the size of lesions, to remove a thrombus or to bypass a severely narrowed or occluded artery. Endarterectomy is a technique by which the atheromatous intima is ‘cored out’ from the underlying media. Embolism of atheromatous debris from the carotid bifurcation is a common cause of transient ischaemic attacks and completed strokes. Controlled trials have shown that carotid endarterectomy reduces the risk of further neurological events. Percutaneous angioplasty is used to ‘crack open’ atheromatous plaques with an inflatable balloon. A metallic expandable stent is usually inserted to maintain the patency of the vessel. These techniques are used in both coronary and lower limb arteries. Surgical bypass procedures use segments of saphenous vein or fabric grafts to divert blood past obstructed segments of lower limb arteries. An atheromatous aneurysm of the distal aorta may be replaced with a Y-shaped fabric graft. Coronary artery stenoses are bypassed with segments of saphenous veins sewn into the proximal aorta or by dissecting the internal mammary artery from the chest wall and anastomosing its distal end to an artery on the anterior surface of the heart, usually the anterior descending branch of the left coronary artery.

Atherosclerotic aortic aneurysms

Atherosclerotic abdominal aortic aneurysms commonly develop in elderly patients (Fig. 13.8). They can be detected by ultrasound examination and the value of screening for these aneurysms is under study. They may impair blood flow to the lower limbs and contribute to the development of peripheral vascular disease. Most importantly, they may rupture into the retroperitoneal space. Elective repair of these aneurysms is comparatively safe but repair after rupture has a high mortality. Some are now managed by percutaneous insertion of supportive stents and this form of treatment may become more common in the future. Aneurysms of the proximal and thoracic aorta are much less common. As with abdominal aneurysms, atherosclerosis is the commonest cause. In atherosclerotic aneurysms there is usually a pronounced loss of elastic tissue and fibrosis of the media. This is due to ischaemia of the aortic media, and release of macrophage enzymes causing fragmentation of elastic fibres. There is evidence that some aortic aneurysms are familial, and inherited defects in collagen have been postulated as the underlying cause.

Fig. 13.8 Atherosclerotic abdominal aortic aneurysm. This large aneurysm was an incidental finding at postmortem. Screening by ultrasound may detect these aneurysms in life.

Aortic dissection (dissecting aneurysms)

In aortic dissection, blood is forced through a tear in the aortic intima to create a blood-filled space in the aortic media (Fig. 13.9). This can track back into the pericardial cavity, causing a fatal haemopericardium, or can rupture through the aortic adventitia. In occasional cases the track re-enters the main lumen to create a ‘double-barrelled’ aorta. The intimal tear and the anatomical features of the aorta can be demonstrated in life by CT or MRI scanning. The underlying pathology is poorly understood. In some, but by no means all, cases there is pronounced degeneration of the aortic media. This is the so-called cystic medial necrosis and is characterised by mucoid degeneration and elastic fibre fragmentation. An exaggerated form of this change is seen in Marfan’s syndrome, a congenital disorder of the expression of a glycoprotein, fibrillin, closely associated with elastin fibres. The strongest risk factor for dissecting aneurysm is systemic hypertension. In some cases the intimal ‘entry’ tears are around atheromatous plaques, but in most cases they involve disease-free parts of the aorta. Without treatment, the mortality from dissecting aneurysm is at least 50% at 48 hours, and 90% within 1 week. The immediate aim of treatment is to contain the propagating haematoma by reducing arterial pressure. Surgical repair is feasible in some patients, especially if the process affects the proximal aorta.

Fig. 13.9 Aortic dissection. A CT scan of a patient with an acute dissection of the ascending aorta. There are two patterns of contrast enhancement in the aorta. The whiter is the main lumen and the greyer the false lumen. The innermost portion of the aortic wall has been peeled away to reveal the underlying haemorrhagic tract.

‘Berry’ aneurysms

In the so-called ‘berry’ aneurysms in the circle of Willis, the normal muscular arterial wall is replaced by fibrous tissue. The lesions arise at points of branching on the circle of Willis, and are more common in young hypertensive patients. The most important complication is subarachnoid haemorrhage (Ch. 26).

Capillary micro-aneurysms

Capillary micro-aneurysms (Charcot–Bouchard aneurysms) are associated with both hypertension and diabetic vascular disease (p. 284). In hypertension, they are common in branches of the middle cerebral artery, particularly the lenticulo-striate. They are thought to be the precursors of primary hypertensive intracerebral haemorrhage, which characteristically occurs in the basal ganglia, cerebellum or brainstem.

Syphilitic aneurysms

Tertiary syphilis is now rare in the developed world but was previously a common cause of proximal aortic aneurysms. They rarely rupture but frequently produce aortic incompetence. The aneurysm is due to ischaemic damage to the media, causing fibrosis and loss of elasticity, secondary to inflammation and narrowing of the vasa vasorum.

Mycotic aneurysms

Mycotic aneurysms are the result of weakening of the arterial wall, secondary to bacterial or fungal infection. The organisms are thought to reach the arterial wall via the blood stream and enter the media via the vasa vasorum. Lesions are commonest in the cerebral arteries (Fig. 13.10) but almost any area can be affected. Bacterial endocarditis is the commonest underlying infection.

Fig. 13.10 Mycotic aneurysm in brain. This patient had infective endocarditis. A mycotic aneurysm (arrow) has ruptured. There is haemorrhage into the basal ganglia, which has extended into the subarachnoid space.

Definition

Hypertension is the commonest cause of cardiac failure in many societies and a major risk factor for atherosclerosis. Furthermore, it is a major risk factor for cerebral haemorrhage, another leading cause of death worldwide. There is no universally agreed definition of hypertension, but most authorities would accept that a sustained resting blood pressure of more than 160/95 mmHg is definite hypertension. Furthermore, this would be categorised as:

Borderline hypertension encompasses the range 140/90 to 160/95 mmHg. In the past, less emphasis was placed on high systolic pressure readings if the diastolic pressure was normal or nearly normal. This is now known to be incorrect practice. Guidelines for the diagnosis and treatment of hypertension are altering as new information becomes available. In the future, treatment is likely to be started at lower blood pressure levels, especially in diabetics.

The diagnosis of an individual patient as hypertensive can be fraught with difficulties. Single blood pressure readings are often spuriously high and many patients have ‘ambulatory’ blood pressure monitoring over a 24-hour period. Care must be taken to ensure that the blood pressure is accurately recorded with an inflatable cuff of appropriate size and shape.

Epidemiology

Hypertension is a serious cause of morbidity and mortality. The incidence of hypertension varies markedly in different countries. In most, but not all, communities, blood pressure tends to rise with age. There is good evidence that high blood pressure is heritable. The precise genetic pattern is not known, but the pattern is polygenic. Blood pressures of parents and their natural children are correlated, whereas those of parents and adopted children are not. The correlation of blood pressures in monozygotic twins is higher than in dizygotic twins. Many black communities, both in western Africa and North America, have a high incidence of hypertension, whereas values tend to be lower on the Indian subcontinent. In certain parts of Africa and the South Pacific, average blood pressures are unusually low. Many epidemiological studies have confirmed a positive correlation between body weight and both systolic and diastolic blood pressure. This association is strongest in the young and middle-aged, but is less predictable in the elderly. Hypertensive patients who lose weight can reduce their blood pressure.

Essential hypertension

Up to 90% of patients who present with elevated blood pressure will have no obvious cause for their hypertension and are therefore said to have essential or primary hypertension (Table 13.2).

Table 13.2 Pathogenesis of systemic hypertension

Secondary hypertensionRenal disease

Endocrine causes

The sympathetic nervous system

Blood pressure is a function of total peripheral resistance and cardiac output; both of these are, to some extent, under the control of the sympathetic nervous system. When compared with controls, patients with essential hypertension have higher blood pressures at any given level of circulating plasma catecholamines, suggesting an underlying hypersensitivity to these agents. The circulating levels of catecholamines are highly variable and can be influenced by age, sodium intake, posture, stress and exercise. Nevertheless, young hypertensives tend to have higher resting plasma noradrenaline levels than age-matched, normotensive controls.

The renin–angiotensin–aldosterone system

Renin is released from the juxtaglomerular apparatus of the kidney, diffusing into the blood via the efferent arterioles (Ch. 17). It then acts on a plasma globulin, variously called ‘renin substrate’ or angiotensinogen, to release angiotensin I. This is in turn converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II is a powerful vasoconstrictor and is therefore capable of inducing hypertension. However, only a small proportion of patients with essential hypertension have raised plasma renin levels, and there is no simple correlation between plasma renin activity and the pathogenesis of hypertension. There is some evidence that angiotensin can stimulate the sympathetic nervous system centrally, and many patients with essential hypertension respond to treatment with ACE inhibitors.

Several therapeutic trials have shown that ACE inhibitors given soon after an acute myocardial infarction decrease mortality, perhaps by preventing myocardial dilatation. Recently, variations or mutations in the genes coding for angiotensinogen, ACE and some of the receptors for angiotensin II have been linked with hypertension.

Dietary sodium and potassium

The role of dietary factors in hypertension is controversial. Hypertension is almost unknown in populations with dietary intakes of sodium of less than 50 mmol/day. In most Western societies daily sodium intakes are above 100 mmol daily, but there is no predictable relationship between intake and blood pressure. Studies in hypertensive patients have shown that a 50-mmol/day reduction in sodium intake reduces systolic blood pressure by 4 mmHg. Human kidneys are efficient at conserving sodium and excreting potassium. This was ideal in prehistoric populations where diets were high in potassium and low in sodium—the converse of the modern Western diets. Fruit and vegetables are rich in potassium as well as polyunsaturated fats.

Renal hypertension

Some forms of acute, and all forms of chronic, renal disease can be associated with hypertension. The two chief mechanisms involved are:

The possibility of renal disease should be considered in all patients with hypertension. In a few cases, a focal stenosis of one renal artery, as a result of atheroma or fibromuscular dysplasia of the renal artery, is responsible for unilateral renal ischaemia and hyper-reninism. Surgical treatment can be curative in selected patients. Patients in terminal renal failure are extremely sensitive to changes in salt and water balance. Hypertension in these patients can often be managed by restriction of salt and water intake and by careful dialysis.

Endocrine causes

The hypersecretion of corticosteroids in Cushing’s syndrome is associated with systemic hypertension. Similarly, adrenal tumours that secrete aldosterone (Conn’s syndrome) or catecholamines (phaeochromocytoma) can cause hypertension. However, these are found in less than 1% of all hypertensive patients.

Coarctation of the aorta

Systemic hypertension is one of the commonest features in coarctation. Raised blood pressure will be detected in either arm, but not in the legs. The femoral pulse is often delayed relative to the radial. Death usually results from cardiac failure, hypertensive cerebral haemorrhage or dissecting aneurysm (see Fig. 13.43).

Drug therapy

Corticosteroids, some types of contraceptive pill and some non-steroidal anti-inflammatory drugs can induce hypertension.

Vascular changes

Hypertension accelerates atherosclerosis, but the lesions have the same histological appearances and distribution as in normotensive subjects. However, hypertension also causes thickening of the media of muscular arteries. This is the result of hyperplasia of smooth muscle cells and collagen deposition close to the internal elastic laminae. In contrast to atherosclerosis, which affects larger arteries, it is the smaller arteries and arterioles that are especially affected in hypertension (Fig. 13.11).

Hypertension increases the normal flow of protein into the vessel wall and the amount of high molecular weight protein, such as fibrinogen, that passes through the junctions between endothelial cells, resulting in protein deposition. These deposits are called hyaline in benign and fibrinoid in malignant hypertension. Hyaline change is a common degenerative feature of many ageing arteries, and refers to the homogeneous appearance of the vessel wall, due to the insudation of plasma proteins. Fibrinoid change is a combination of fibrin with necrosis of the vessel wall. There is no evidence that an immunological reaction is involved in hypertensive vascular disease.

Heart

Hypertension accelerates atherosclerosis, thus ischaemic heart disease is a frequent complication. A large, ongoing longitudinal population study in Framingham, Massachusetts, has shown hypertension to be a major cause of cardiac failure in previously fit subjects. The left ventricle undergoes hypertrophy and may ‘outgrow’ its blood supply, particularly if there is associated coronary atherosclerosis. Patients with hypertensive left ventricular hypertrophy are more liable to spontaneous arrhythmias than normal subjects. The decreased prevalence of systemic hypertension and left ventricular hypertrophy in Western populations has been attributed to the increasing use of antihypertensive medications.

Nervous system

Intracerebral haemorrhage is a frequent cause of death in hypertension. There is good evidence that effective control of blood pressure reduces the risk of hypertensive cerebral haemorrhage.

Kidneys

The degree of renal damage due to glomerular sclerosis or necrosis varies considerably from patient to patient. Proteinuria may be a complication of benign hypertension, while renal failure is a characteristic of the malignant phase.

Pathogenesis

Vasculitis is the name given to inflammatory diseases of blood vessels. The cause of most forms of vasculitis is unknown but clinical and experimental studies suggest that in some cases the underlying pathology is a deposition of complexes of antigen and antibody in the vessel wall. Immune complexes are not inherently harmful, but if they lodge in tissues and activate complement they incite an acute inflammatory reaction and trigger the coagulation system. Repeated minor trauma may be the reason that the lesions of some vascular disorders develop on the extensor surfaces of the arms and on the buttocks (Fig. 13.14). Venous stasis may account for the fact that some examples of vasculitis are particularly prominent in the lower leg.

Fig. 13.14 Henoch–Schönlein purpura. Note that the lesions in this 20-year-old man are most prominent on the buttocks and elbows, sites of everyday trauma. In this condition IgA is usually demonstrated in the walls of affected vessels.

Clinicopathological features

In most forms of vasculitis the pathological changes in the vessels are broadly similar. A dense infiltrate of acute and chronic inflammatory cells is usually present and in some instances immunological techniques may demonstrate abnormal deposits of immunoglobulin and complement in the intima and media. The patterns of disease in vasculitis are largely a result of the organ and the size of the vessel affected. Because of this, systemic vasculitis can present with a wide variety of different signs and symptoms. Pathologists prefer to classify vasculitis according to the type and size of vessel that is chiefly involved. The major clinical and pathological features of some common immunological vascular disorders are summarised in Table 13.4.

A skin rash is one of the commonest presenting features of acute vasculitis, and is sometimes closely related to treatment with a particular drug. In these circumstances the foreign substance probably acts as a hapten in the induction of an immunological reaction. Many forms of vasculitis are self-limiting, but their clinical course can sometimes be shortened by anti-inflammatory drugs. When the disease affects several different organs and systems the term systemic vasculitis is used. Examples include polyarteritis nodosa (Fig. 13.15), rheumatoid vasculitis and Wegener’s granulomatosis. Without treatment the prognosis in systemic vasculitis is poor. The possibility of systemic vasculitis must be considered in any patient with a multisystem pattern of illness, especially if the respiratory tract is involved. Anti-inflammatory and cytotoxic drugs, such as steroids and cyclophosphamide, may induce clinical remissions in 75% of patients.

Fig. 13.15 Polyarteritis nodosa. Fibrinoid necrosis and heavy inflammatory cell infiltration in a medium-sized artery in a patient with polyarteritis nodosa.

Complications

Complications of vasculitis include thrombosis with resulting ischaemia or infarction. Multiple sites are usually involved simultaneously. Tissues with a high blood flow, such as the skin and the glomeruli, are preferentially affected.

In many patients with these disorders there are increased levels of circulating immune complexes, and the complement concentrations may be low, particularly when the disease is active. Auto-antibodies are present in some patients (Table 13.4). Some are directed against components of vascular endothelial cells (anti-neutrophil cytoplasmic antibodies—ANCA) and are useful in supporting a clinical diagnosis.

Acute and chronic failure

The clinical features of heart failure depend on the rapidity with which the underlying pathological changes develop. For example, acute failure can occur within minutes of a myocardial infarct. Typically, the patient presents with sudden severe shortness of breath and marked pulmonary oedema. In contrast, valvular defects, such as mitral stenosis and some forms of mitral incompetence, may develop over a period of years and the patient may describe only a very gradual worsening of symptoms. Not infrequently, chronic congestive heart failure develops after an episode of acute failure, for example after a myocardial infarct.

Right and left heart failure

Because the right and left ventricles share an interventricular septum and function together in a closed circuit, it is inevitable that the failure of one ventricular chamber is followed by a failure of the other. Nevertheless, in the early stages of cardiac failure, the clinical signs and symptoms may appear ‘one-sided’. The immediate consequence of left heart failure is pulmonary congestion and oedema. In contrast, right heart failure may produce prominent systemic venous congestion, raised jugular venous pressure and enlargement of the liver. The term cor pulmonale is used to describe right heart failure secondary to lung disease. The commonest cause of cor pulmonale is chronic obstructive airway disease (chronic bronchitis and emphysema). As lung tissue is destroyed, the pulmonary capillary bed is progressively reduced. Effectively the normal cardiac output is pumped into a smaller number of vessels and pulmonary pressure rises. Hypoxia causes reflex pulmonary vasoconstriction and further elevates pulmonary vascular resistance. Just as the left ventricle may fail in systemic hypertension, the right ventricle fails when pulmonary pressures are persistently elevated. Another cause of increased pulmonary pressure and right heart failure is mitral stenosis. In congestive cardiac failure, there is both right and left ventricular failure and a full combination of systemic and pulmonary signs.

Other terminologies in heart failure

In most patients with heart failure, cardiac output fails to increase, or may even decline during exercise, and eventually it is decreased even at rest. This is termed low output failure and is the direct consequence of the inability of the heart to pump normally. In contrast, a few patients may develop pulmonary congestion and oedema when the total cardiac output and ejection fraction of the left ventricle is normal or even increased. This is termed high output failure. The causes of this include an increase in blood volume, for example during pregnancy or from accumulation of excess salt and water due to salt-retaining steroids. It is also associated with an abnormally increased venous return and/or decreased peripheral resistance, for example in hyperthyroidism, cirrhosis, renal failure and severe anaemia.

Because echocardiography is the most sensitive and specific method of diagnosing heart failure, an increasing number of patients have a transthoracic ‘echo’. In the majority of established cases the proportion of blood ejected at each heart beat (the ejection fraction) is reduced. This is termed systolic failure. In some patients systolic function is more normal but there is impaired diastolic filling of the ventricles. This is now called diastolic failure and is increasingly recognised in elderly hypertensive patients.

Dyspnoea

Except after exercise, breathing is normally automatic and effortless. Dyspnoea is the subjective symptom of shortness of breath or difficulty in breathing and is usually the first symptom of heart failure. Because it is such an important and distressing symptom it has been studied in great detail. Despite this, its exact cause is not understood. In advanced heart failure there is an increase in both the blood and water content of the lungs, and this must be at the expense of the air volume. Intense dyspnoea follows acute left ventricular failure, for example after acute myocardial infarction. The abrupt rise in pulmonary venous pressure causes massive transudation of fluid from the capillaries into the interstitial tissues of the lung, the alveoli and terminal alveoli. Pink frothy fluid pours out from the mouth and nose, and crackles can be heard with a stethoscope, especially in the dependent parts of the lungs.

Shortness of breath while lying flat (orthopnoea) and paroxysmal nocturnal dyspnoea are characteristic signs of left ventricular failure. The basis of orthopnoea is the increased venous return from the legs and gastrointestinal veins to the lungs that results from lying flat. In paroxysmal nocturnal dyspnoea there is a sudden and urgent shortness of breath during sleep, probably because of progressive pulmonary venous congestion.

Increased pulmonary venous pressure and chronic heart failure cause recurrent episodes of alveolar haemorrhage. Some patients in heart failure cough up rusty brown or obviously bloodstained sputum. The rusty colour is the result of haemosiderin-laden macrophages.

Systemic venous congestion and oedema

Fluid retention by the kidney is a compensatory mechanism in cardiac failure. This produces an increased venous return, an increase in ventricular preload and ‘volume overloading’ of the ventricles. Veins are the reservoir for an increased blood volume, and in established heart failure there is widespread congestion of the systemic veins. Distension of the superficial jugular vein in the semi-erect position is one of the earliest signs of this. In congestive heart failure, the liver is enlarged as a direct consequence of engorgement of the centrilobular veins and hepatic sinusoids. The associated ischaemia causes fatty change in hepatocytes (Fig. 13.21). In prolonged cardiac failure, liver function tests can be abnormal, and slight increases in serum bilirubin and transaminases are not uncommon. Dilatation of the left ventricle may be a prominent radiological and echocardiographic feature (Fig. 13.22).

Fig. 13.21 Liver in heart disease. Liver from a patient who died with severe congestive heart failure. Alternating zones of pale fatty change and dark congestion produce a ‘nutmeg’ liver.

Fig. 13.22 Chest X-ray in congestive heart failure. Note the marked dilatation of the heart (arrow), as compared with the normal chest X-ray in Figure 13.2B, and the increased opacity of the lungs due to congestion and oedema.

A variety of factors contribute to the accumulation of fluid in subcutaneous tissues and in the pleural, pericardial and peritoneal cavities. A hydrothorax is a pleural effusion composed of transudated fluid of low protein content. It is a common feature of congestive cardiac failure, but is rare in uncomplicated left heart failure. High systemic venous pressure is not only responsible for the increased transudation of fluid from pleural capillaries, but also impairs drainage from the lymphatics and the thoracic duct. Large pleural effusions also contribute to the dyspnoea of heart failure. Pericardial and peritoneal effusions (ascites) are features of severe congestive failure.

Other pathophysiological changes

Clinical features

The most frequent symptom of acute myocardial infarction is severe chest pain. This often develops suddenly but may build up gradually, and generally lasts for several hours. Pain is usually accompanied by profuse sweating, nausea and vomiting. Many patients give a previous history of angina or of non-specific chest pain in the weeks before the acute event. In at least 10% of patients, myocardial infarction is painless or ‘silent’; this is particularly true in the elderly.

Patients who are admitted with acute chest pain have a variety of underlying pathological changes. These include chronic coronary artery narrowing, rupture or erosion of coronary plaques, acute coronary thrombosis and acute myocardial infarction. The ECG gives a good guide as to which coronary artery is narrowed and the extent of myocardial damage. Acute infarcts are now classified according to the presence or absence of ST-segment elevation. Infarcts with ST elevation on the initial ECG (STEMIs) require emergency treatment to reopen the obstructed coronary artery. This may be achieved with drugs that activate the plasminogen system. Increasingly these patients are treated with emergency angioplasty to reopen the obstructed artery physically. Patients with chest pain but no evidence of ST-segment elevation require emergency estimation of troponin, a cardiac muscle protein that is released into the circulation after cardiac muscle cell death. Significantly increased levels indicate a so-called non-STEMI infarct. In these patients it is thought that the infarct is limited largely to the subendocardial zone of the myocardium. However, detailed clinicopathological studies linking the precise pattern of infarction with ECG changes are difficult to complete in the era of declining autopsy rates. Patients with severe chest pain but no ECG or biochemical evidence of infarction are said to have unstable angina. The underlying pathological change is thought to be rupture or erosion of a plaque of coronary artery atheroma.

Morphology

The location and size of the infarct depend on:

In clinical practice the ECG changes give a good guide to the area of myocardium that is infarcted (Fig. 13.24).

Fig. 13.24 Myocardial infarction. Obstruction of each major coronary artery results in infarction of specific areas of the myocardium.

When coronary angiography is performed in patients with typical symptoms and signs of acute myocardial infarction, a complete obstruction of a major coronary artery can be demonstrated in up to 90% of cases. The immediate objectives of treatment are to relieve pain with opiate analgesia and to restore blood flow in the occluded artery. Activation of the plasminogen system with recombinant forms of human plasminogen activator will partially lyse thrombi and improve blood flow in the occluded artery in at least 50% of patients. Emergency coronary angioplasty is also effective at breaking down thrombi and restoring blood flow. It is used as a primary treatment for coronary thrombosis in most centres worldwide.

The macroscopic and microscopic changes of myocardial infarcts follow a predictable sequence (Table 13.5). The chief features are necrosis, inflammatory cell infiltration and, as cardiac muscle cannot regenerate, repair by fibrous tissue. The extensive necrosis of cardiac muscle is associated with the release of cardiac enzymes and proteins into the circulation. A rapid bedside test for the diagnosis of acute infarction would allow more rational use of thrombolytic drugs or emergency angioplasty. Assays for the blood level of the cardiac muscle protein troponin are the most reliable early biochemical indicator of acute myocardial infarction but may not be increased for some hours after the onset of pain. Raised serum levels of creatine kinase also suggest acute myocardial infarction. Neither of these markers is entirely specific for myocardial infarction. Most patients show a transient leukocytosis in the first 1–3 days, but the value rarely exceeds 15 × 10⁹/l. In clinical practice this is of limited value, largely because of the many other causes of a transient leucocytosis.

Table 13.5 Macroscopic and microscopic features of myocardial infarcts

Complications

The complications of myocardial infarction are listed in Table 13.6, and see Figures 13.25 and 13.26.

Table 13.6 Complications of myocardial infarcts

Fig. 13.25 Mural thrombus. Many layers of thrombus have formed on the infarcted myocardium. This can fragment and embolise.

Fig. 13.26 Healed myocardial infarction. Note that the ventricular wall is very thin at the apex of the heart where there is a white fibrous scar.

Early detection and prompt treatment of complications are important in the management of patients with myocardial infarction. Cardiac arrhythmias, sometimes leading to ventricular fibrillation and sudden death, are frequent in the first 24–48 hours after the initial infarct. Cardiac rupture produces electromechanical dissociation (pulseless electrical activity) and rapid death (Fig. 13.27). The incidence of this important complication has been reduced by thrombolytic therapy. Pericarditis, mitral incompetence and cardiac failure are the important complications in the first week after infarction. Later complications include embolism from mural thrombus formation, and the development of ventricular aneurysms.

Fig. 13.27 Sudden death following rupture of an acute anterior myocardial infarct. There was a large haemopericardium and the patient died from cardiac tamponade.

As with all patients who are immobilised, there is a substantial risk of deep venous thrombosis and the possibility of subsequent pulmonary embolism. Prolonged bed rest is not essential for cases of uncomplicated myocardial infarction, and early mobilisation has done much to reduce the incidence of post-infarction pulmonary embolism.

Clinical features

Angina is one of the commonest clinical features of patients with a long history of ischaemic heart disease. A history of chest pain, induced by exercise and relieved by rest, should be sought in any patient in whom ischaemic heart disease is suspected. Impaired left ventricular function, following one or more previous episodes of myocardial infarction, may result in left ventricular and, ultimately, congestive cardiac failure. Some patients present with severe or rapidly progressive anginal chest pain. This is termed unstable or crescendo angina. It may progress to myocardial infarction and requires emergency management.

Morphology

Most patients with a definite clinical history of angina have extensive coronary arterial atheroma. Typically, two or three of the major coronary arteries have patches of stenosis in which the lumen is reduced to less than 75% of its normal cross-sectional area (Fig. 13.28). Careful postmortem studies in patients who have died after episodes of unstable angina have demonstrated recent rupture of the fibrous cap of large, often eccentric and lipid-rich atheromatous plaques. Paradoxically some patients with a typical clinical history of angina have relatively normal coronary angiograms. It may be that the recurrent episodes of coronary spasm are responsible for pain in these patients; this is sometimes called ‘variant angina’.

Fig. 13.28 Postmortem coronary angiograms. Normal; note the widely patent right coronary artery, upper left. The contours of the right coronary are irregular and there is a complete obstruction of the circumflex branch. Coronary angiograms made in life do not demonstrate all the small vessels shown above.

Postmortem examinations on patients with a long history of ischaemic heart disease frequently demonstrate areas of healed myocardial infarction, dilatation of the left ventricle, and other changes related to chronic heart failure such as peripheral oedema, pleural and peritoneal effusions, and pulmonary oedema and congestion.

Aetiology

Acute cardiac failure as a result of ischaemic heart disease is one of the commonest diagnoses made by pathologists in cases of sudden unexpected death. In many cases, significant narrowing of one or more coronary arteries is identified. When detailed radiological and histological studies are made in patients dying within 6 hours of the onset of ischaemic symptoms, a coronary thrombosis can be found in approximately 55% of cases. At this stage, however, there will be no associated macroscopic or histological evidence of recent myocardial infarction. In the remainder of cases due to ischaemic heart disease there is severe narrowing of one or more coronary arteries, with or without evidence of previous healed myocardial infarction. It is assumed that these patients have died from a ventricular arrhythmia. Pathologists rely on the police evidence that there are no suspicious circumstances. About 50% of patients with established cardiac failure die suddenly, while the remainder deteriorate gradually. Sudden death is also a feature of patients with all forms of cardiomyopathy.

Other common causes of sudden death include ruptured atherosclerotic aneurysms of the abdominal aorta, dissecting aortic aneurysms and pulmonary emboli. Aortic stenosis is a cause of Stokes–Adams (‘drop’) attacks and can also lead to sudden death; acute coronary insufficiency is the probable mechanism (Fig. 13.29). Rupture of a berry aneurysm in the circle of Willis or massive intracerebral haemorrhage from a capillary micro-aneurysm may lead rapidly to death. Despite careful postmortem examination and toxicology, the cause of sudden unexpected death is sometimes not determined. This is increasingly recognised and is sometimes termed sudden adult (or arrhythmic) death syndrome (SADS). In a proportion of these cases biochemical abnormalities in sodium or potassium channels in cardiac muscle have been demonstrated, some of which are due to heritable mutations. It is therefore essential that relatives of sudden cardiac death victims are screened for cardiac abnormalities.

Fig. 13.29 Aortic stenosis. This 58-year-old male died suddenly. Note that the valve is bicuspid and nodular due to heavy calcification. This is the more typical pattern of aortic stenosis in a tricuspid aortic valve. Again there are heavy nodular areas of calcification.

Prevention

Ventricular fibrillation is often the immediate cause of death in patients with acute ischaemic heart disease. Many ambulance crews now carry a defibrillator and administer DC shock to appropriate patients en route to hospital. Defibrillators are also installed in public areas such as football grounds and railway stations and are carried in some aircraft. There is good evidence from community studies that prompt cardiopulmonary resuscitation can prevent death in such circumstances. Patients with a history of ventricular arrhythmias can be treated with an implantable defibrillator that senses ventricular fibrillation and automatically delivers a defibrillating shock. Guidelines for the insertion of these devices have been developed and implantation rates are increasing. In some cases cardiac electrophysiologists can ‘map’ the pattern of electrical activity within the ventricle and, using a radiofrequency electrode, ablate the segment of myocardium that is responsible for abnormal electrical impulses.

Pulmonary embolism causes many tragic deaths, sometimes in previously fit patients in the post-operative period. Early mobilisation helps to minimise the risk of deep venous thrombosis. Anticoagulant therapy reduces the incidence of venous thrombosis and subsequent embolism, and patients at high risk of developing venous thrombi are sometimes treated prophylactically.

Patients with prosthetic heart valves

Up to 2–3% of patients with artificial heart valves develop endocarditis (Fig. 13.35). Staphylococci account for at least 50% of cases. Many of these are coagulase-negative.

Fig. 13.35 Prosthetic valve endocarditis. This patient had a mitral valve replacement 5 months previously but developed prosthetic valve endocarditis. Note the large vegetations forming at the margins of the tilting discs. Fortunately this patient recovered. This patient underwent mitral valve replacement 7 months before death. Vegetations have virtually obscured the underlying prosthetic valve.

The commonest initial presenting symptom is post-operative fever. When residual wound sepsis and pulmonary or urinary tract infections have been excluded, prosthetic valve endocarditis should be seriously considered. Typically the process develops about 2 months after valve replacement. Echocardiography and repeated blood cultures are essential for diagnosis. Despite medical and surgical treatment, the mortality rate can be as high as 70%. In some patients, prosthetic valve endocarditis develops many months or years after the operation, and this possibility should always be considered in a pyrexial patient who has had a previous valve replacement.

The elderly

Endocarditis is increasing in incidence in elderly patients. Calcific valve disease is the most frequent pathology. Predisposing factors include genito-urinary infection, diabetes, tooth extraction, pressure sores and surgical procedures. It appears that virulent organisms such as Staph. aureus may be more frequent as the infecting organism in elderly patients. Complications also appear to be more common than in younger patients. Presenting signs and symptoms are often atypical because of other co-existing disease processes, such as respiratory tract infection and cardiac failure.

Drug addicts

Infective endocarditis in drug addicts has increased in all Western societies. The skin is the most common source of micro-organisms; most cases are due to Staph. aureus or Staph. epidermidis, and fungi such as Candida. The bacteraemia has various causes:

Very few intravenous drug abusers presenting with their first episode of endocarditis have previously damaged heart valves. Perhaps the repeated intravenous injection of ‘foreign’ material damages the endocardial surfaces, producing abnormal (roughened) areas. These become sites of platelet aggregation and therefore the development of vegetations. This may account for the high incidence of tricuspid valvular involvement in drug addicts, as this valve is closest to the injection site.

Vegetations in drug addicts are often large, particularly in fungal endocarditis. As infection primarily involves the right side of the heart, vegetations can embolise to the lungs. Endocarditis must be suspected in any drug addict presenting with signs or symptoms of pneumonia, pulmonary embolism or infarction.

Local effects

All but the smallest vegetations have some effect on valvular function, and many cause valvular incompetence. A heart murmur is one of the most important physical signs of infective endocarditis. As the vegetations enlarge, valve cusps can perforate or chordae tendineae rupture. This is one cause of death in endocarditis and is now one of the indications for valvular replacement. Myocarditis is an important complication of endocarditis; the inflammation probably spreads directly from the valve leaflet to involve the annulus and adjacent myocardium. Vegetations can embolise to coronary arteries but this is extremely uncommon.

Systemic effects

Fever, weight loss, malaise and splenomegaly are the classical findings in infective endocarditis and can be attributed to the persistent bacteraemia. Parts of the vegetations may break away from the heart valves and lodge in many different sites; the spleen, kidney and brain are those most frequently involved. Small emboli produce tiny haemorrhagic lesions, essentially small infarcts, in the skin, mucous membranes and retina. Linear haemorrhages beneath the tips of the nails (splinter haemorrhages, Fig. 13.37A) are frequent in infective endocarditis, but equally can follow everyday trauma. Clubbing (Fig. 13.37B, C) is another clinical feature; its cause is unknown. It is also known as Schamroth’s sign after the physician who described the changes in his own fingers while suffering from endocarditis.

Fig. 13.37 Changes in the hands and nails in infective endocarditis. Prominent splinter haemorrhages. Normal nail beds. Clubbing in infective endocarditis. This is sometimes known as Schamroth’s sign. There are of course many other causes of clubbing, including pulmonary carcinoma, intrathoracic infections and congenital heart disease.

A focal segmental glomerulonephritis can be seen in infective endocarditis. This is almost certainly the result of immune complex deposition in glomeruli (Ch. 21). The antigen is probably derived from the micro-organism and the antibody produced by the host in response to it. Some other manifestations of infective endocarditis, such as Osler’s nodes in the fingers, may be the result of an immune complex arteritis in the soft tissues.

Investigations

Once a diagnosis of infective endocarditis has been considered, two lines of investigation are essential. The heart valves must be imaged by trans-thoracic or trans-oesophageal echocardiography, and the organism must be cultured from the blood stream. Delay in either of these may have serious consequences and their importance cannot be overemphasised. Echocardiography is valuable in identifying vegetations at initial presentation, for following how their size changes with treatment and for selecting cases for surgical treatment (Fig. 13.38).

Fig. 13.38 Echocardiographic appearance of valve vegetations. In this case the vegetations are on the tricuspid valve (arrowed). The patient was an intravenous drug abuser.

It is important to isolate the causative organism from the blood stream. This not only establishes the diagnosis but indicates which antibiotic or combination of drugs is needed to destroy the infecting organism. In taking blood cultures, it is essential to prevent skin and airborne bacteria contaminating the blood sample. Particular care should be taken to sterilise the skin overlying the vein, using a strong antiseptic such as chlorhexidine in 70% ethanol. Up to one-quarter of blood cultures grow skin bacteria, and this can lead to erroneous diagnoses and inappropriate treatment. Release of bacteria from vegetations is probably episodic and the numbers released may be small. Multiple blood cultures should be taken each day, perhaps for two or even three days. In practice, patients are often so ill that treatment must be started as soon as the diagnosis is suspected clinically, and certainly before the results of blood culture are available. In around 5% of patients with good clinical evidence of endocarditis blood cultures are negative. Failure to recover the causative organism can be due to:

Treatment

Ideally patients should be treated in a cardiac unit with ready access to cardiac surgery. Without adequate antibiotic treatment endocarditis is uniformly fatal. The avascular structure of the vegetation prevents the invasion of large numbers of phagocytes, and because of this it is essential to sterilise the heart valve with antibiotics. The antibiotics chosen must kill the bacteria, not just inhibit their growth. Cardiologists and microbiologists work closely together to select the most appropriate combination and dosages of antibiotics. Serial echocardiography is used to assess the change in size of vegetations. Surgical replacement of valves is increasingly used, especially if vegetations do not reduce in size with antibiotic treatment.

Prevention

Any patient with valvular heart disease is at risk of developing endocarditis as a result of bacteraemia associated with even the most minor surgical or dental procedure. It is therefore essential that the blood contains a high concentration of bactericidal antibiotics immediately before and during these procedures. The aim is to kill bacteria in the blood stream before they settle on the heart valve. Endocarditis still has an appreciable mortality, and the importance of these prophylactic measures cannot be overemphasised. Tragically, cases of endocarditis still occur in previously fit individuals not given appropriate antibiotic cover during minor procedures.

Acute pericarditis

In acute pericarditis there is invariably a fibrinous exudate on the pericardial surfaces, with associated acute inflammation (Fig. 13.39). In many cases, there is an exudate of serous fluid (pericardial effusion) and this may become haemorrhagic. Common viral causes include coxsackievirus A and B, herpes simplex and influenza. Bacterial pericarditis results either from direct spread from an intrathoracic focus or from a blood stream infection.

Fig. 13.39 Acute pericarditis. Acute fibrinous pericarditis. Note the granular masses of fibrin on the visceral pericardial surface. Common causes of pericarditis include acute myocardial infarction, uraemia, viral infections and recent cardiac surgery. This patient had a cardiac bypass procedure 7 days before his death. The vein graft is arrowed.

Chronic pericarditis

Chronic pericarditis may have no obvious cause but is a feature of connective tissue diseases such as rheumatoid arthritis, and of tuberculosis. In many cases an effusion develops and there is marked fibrous thickening of the pericardial layers. Many patients with a previous history of myocardial infarction have areas of old pericardial fibrosis, the result of healing of previous acute pericarditis.

Clinicopathological features

Typically, patients with pericarditis complain of chest pain, which may be either sharp or dull and aching. Young patients who present with acute non-specific or viral pericarditis often have severe chest pain which can be confused with acute myocardial infarction. Severe pain is uncommon in other forms of pericarditis. A pericardial friction rub is a characteristic feature of acute fibrinous pericarditis, but it may be transient and variable in its intensity. Pericardial effusions of less than 50 ml are usually undetectable clinically. With large effusions, the area of cardiac dullness to percussion is increased and the heart sound may be diminished. Echocardiography is essential for correct diagnosis. Large effusions may interfere with diastolic filling of the heart and produce cardiac tamponade. The jugular venous pressure is raised, and there is an exaggerated variation in pulse pressure during inspiration and expiration (pulsus paradoxus). Characteristic pressure tracings may be obtained during cardiac catheterisation. Constrictive pericarditis may seriously impair cardiac function, and surgical excision of the pericardium may improve cardiac output. In many cases there is associated calcification of the pericardium, which may be seen on chest X-rays, particularly lateral views.

Pathogenesis

The chief causes of inflammation of the myocardium are:

Coxsackie B virus is the commonest known infectious cause of pericarditis and myocarditis in western Europe and North America. The diagnosis is suggested by rising titres of specific antibodies in the serum. Many other viruses have been implicated. Diphtheria has not been eradicated from developing countries and cardiac failure is a frequent cause of death; an exotoxin inhibits protein synthesis in cardiac muscle. Myocarditis can complicate infective endocarditis and in some cases myocardial abscesses form around valve rings.

Clinicopathological features

In most patients myocarditis is a self-limiting condition with only mild pleuritic chest pain. Fatalities are relatively uncommon (Fig. 13.40). In some patients cardiac failure develops and coronary angiography may be performed to exclude coronary artery disease. An endomyocardial biopsy may be performed at the same time and may show lymphocytic infiltration and myocyte necrosis. However, even in the most typical clinical cases the proportion of positive biopsies is small. Viral or molecular studies may identify an underlying causative agent. Anti-inflammatory drugs may be used in severe myocarditis but there is no definite evidence that they are effective.

Fig. 13.40 Coxsackievirus myocarditis. This heart is from a 19-year-old female who was fit 6 months before her death. Note the marked thinning of the right ventricular wall and the areas of adherent mural thrombus.

Aetiology

Congenital cardiovascular disease is the result of a structural or functional abnormality of the cardiovascular system at birth. In the vast majority of cases, the structural defects can be attributed to a specific disturbance of normal embryological development.

The incidence of congenital heart disease (CHD) is around 8 per 1000 live births and is much higher if bicuspid aortic valves are included. In about one-third of cases critical illness develops early in life. Associated extracardiac abnormalities occur in about a quarter of infants with CHD. In Down’s syndrome, for example, there is a high incidence of atrial or ventricular septal defect, or a patent ductus arteriosus.

In at least 80% of cases the cause of congenital heart disease is unknown. Environmental factors, such as maternal viral infections (especially rubella), chronic maternal alcohol abuse and drugs such as thalidomide, are all clearly related to CHD. These factors are of greatest importance between the fourth and ninth weeks after conception. During this period, the common atrial and ventricular chambers are divided by septa, the cardiac valves develop and the primitive truncus arteriosus divides into the aorta and pulmonary artery. The incidence of CHD is somewhat increased in the children of mothers with insulin-dependent diabetes or phenylketonuria.

There is a weak but definite family incidence of congenital cardiovascular disorders and the genetic basis of these defects is under investigation. Some congenital heart defects are associated with extracardiac abnormalities and in a small number of these specific chromosomal abnormalities have been detected. The risk of a congenital heart lesion in the siblings of affected individuals varies with the nature of the defect, for example from 2% for coarctation of the aorta to over 4% for ventricular septal defects. When two or more members of a family are affected, the risk appears to be substantially higher and, in these instances, clinical geneticists may be able to provide advice to parents.

Clinicopathological features

Some of the most prominent clinical and pathological features of CHD are:

Most children under 1 year of age who present with cardiac failure have a structural abnormality of the cardiovascular system. The severity of cardiac failure and the presence or absence of additional signs, such as cyanosis, depend on the precise structural abnormalities. Echocardiography and cardiac catheterisation now permit a detailed understanding of disordered anatomy before cardiac surgery.

Atrial septal defects (ASD)

Between the fourth and seventh weeks of fetal life two distinct flaps of tissue develop to divide the common cavity into the left and right atria. The first, the septum primum, has two defects but these are normally covered when the second partition, the septum secundum, grows upwards from the atrioventricular ring. The higher of these defects, the ostium secundum, is covered by a flap of the septum secundum. In fetal life this acts as a flap valve, allowing blood entering the right atrium from the systemic veins to bypass the lungs by flowing into the left atrium. When the pulmonary circulation is established, it closes, and in most cases the two layers of the flap fuse together. In many children and some adults a probe can be passed between the layers, the so-called ‘probe patent’ foramen ovale. A defect in this area is the usual form of atrial septal defect (ASD). Less common types of ASD are related to defects low in the interatrial septum, close to the atrioventricular ring. There may be associated abnormalities in the mitral valve, and surgical repair is more complex. Other uncommon types of ASD are associated with defects in the development of the pulmonary veins or the coronary sinus.

Atrial septal defects make up approximately 10% of all congenital abnormalities of the heart. Although they are often asymptomatic, in the past many untreated patients developed signs of right heart failure in the third and fourth decades. A diastolic rumbling murmur, due to increased flow across the tricuspid valve, may be heard and, because of delayed closure of the pulmonary valve, there is often wide splitting of the second heart sound. The right ventricle is compliant and easily dilates to accommodate the increased pulmonary blood flow, but right ventricular hypertrophy and pulmonary hypertension inevitably develop. Closure is therefore indicated.

Ventricular septal defects

Ventricular septal defects account for approximately 25% of all cases of congenital heart disease in infancy. A variety of anatomical forms are recognised and their size and position can be estimated by echocardiography. Small defects in the muscular wall may close spontaneously as the heart grows. Surgical closure is indicated for larger muscular defects and those involving the membranous (fibrous) portion of the septum, close to the atrioventricular ring (Fig. 13.41). As the left ventricular pressure is substantially greater than that in the right, there is always some shunting of blood through the defect. The size and site of the ventricular defect determine the extent of this shunt. In some cases, defects in the membranous septum are also associated with valvular abnormalities, particularly aortic incompetence, and this influences the clinical presentation.

Fig. 13.41 Ventricular septal defect. This child was 4 years old at the time of his death. He had marked left ventricular hypertrophy. This is the heart of a child who died in Africa in the 1970s. Ideally lesions such as these should be treated surgically within the first year of life.

The most prominent physical sign of ventricular septal defect is a loud pansystolic murmur, often with an associated thrill. The most important complication is cardiac failure but there is also a risk of infective endocarditis.

Patent ductus arteriosus

In fetal life, the pulmonary vascular resistance is high and the right heart pressure exceeds that of the left. Consequently there is a flow from the right to the left atrium through the foramen ovale, and from the pulmonary artery to the aorta via the ductus arteriosus. At birth, the pulmonary vascular resistance declines dramatically, and the ductus arteriosus closes within the first few days of life. If the ductus remains open (patent), there is an abnormal shunt of blood from the aorta to the pulmonary artery. This increases both pulmonary arterial and left heart blood flow, but the right atrium and ventricle are virtually unaffected (Fig. 13.42).

Fig. 13.42 Circulation in patent ductus arteriosus. The duct should normally close very soon after birth. (LCC, left common carotid artery; LSC, left subclavian artery; PA, pulmonary artery.)

As in ventricular septal defects the symptoms are proportional to the size of the left-to-right shunt. A continuous ‘machinery’ murmur is characteristic, and is loudest at the time of the second heart sound. If the shunt is large, a left ventricular impulse (‘heave’) is usually present. If a patent ductus does not close spontaneously, surgical treatment is indicated. In all forms of aortic surgery pre-operative echocardiographic and angiographic investigations are used to define the precise anatomy of the aortic arch and its branches.

Coarctation of the aorta

A congenital localised constriction in the diameter of the aorta is known as a ‘coarctation’. This defect accounts for up to 5% of all forms of congenital cardiovascular disease and is substantially more common in males. In the usual form of coarctation the narrowing occurs just distal to the ductus arteriosus, which is usually closed. In a proportion of cases there are associated aortic valve abnormalities, usually a congenitally bicuspid valve.

The signs and symptoms are largely dependent on the degree of constriction (Figs 13.43 and 13.44). If this is severe, symptoms develop soon after birth. If the coarctation is undetected or untreated, a collateral circulation develops to increase blood flow to the lower part of the body. This process involves branches of the intercostal arteries, which become dilated and tortuous. In time, the enlarged vessels may erode portions of the rib, producing ‘notching’ on chest X-ray. The most characteristic clinical finding is hypertension in the upper limbs, with a much lower pressure in vessels distal to the coarctation. The intensity of the femoral pulse is often much reduced. The abnormal blood flow through the coarcted segment may produce a systolic murmur, best heard in the posterior chest.

Fig. 13.43 Coarctation of the aorta: clinical features. Echocardiography now detects most cases early in life. The diagnosis should be considered in any child who fails to thrive.

Fig. 13.44 Coarctation of the aorta. Left: A section of an aorta from a 3-day-old child. Note that the lumen of the aorta is less than 2 mm in diameter. Right: A specimen from a 24-year-old male who was found to be hypertensive. The aortic lumen is approximately 5 mm in diameter. Note that atherosclerosis has formed proximal to the coarctation because of turbulent blood flow.

Some patients with coarctation are asymptomatic but most die prematurely, usually as a result of:

In view of these complications, and the shortened life-span of many patients, surgical treatment is usually indicated.

Complex congenital heart disease

These are rare disorders in which individual cardiac chambers are imperfectly developed or incorrectly connected. An exact diagnosis is made by defining the anatomical features using cardiac ultrasonography or other radiological techniques. These disorders usually present soon after birth and a wide range of corrective or palliative surgical techniques have been developed.

The commonest of the complex abnormalities is Fallot’s tetralogy, first described in Marseilles in the 19th century. The four components are:

The clinical features are often characteristic. As the aorta receives both oxygenated blood from the left ventricle and deoxygenated blood from the right, cyanosis develops. Pulmonary stenosis restricts blood flow from the right ventricle into the lungs and, if this is severe, survival is only possible if the ductus arteriosus remains open. The systolic murmurs result from either the ventricular septal defect, or, if severe, the pulmonary stenosis. As in all hypoxic patients, the haemoglobin concentration is increased. Right heart failure is inevitable and bacterial endocarditis can ensue. Dyspnoeic children with Fallot’s sometimes adopt a characteristic squatting posture, with both the knee and hip joint sharply bent, or sit in a ‘knee–chest’ position. This may be an attempt to increase venous return from the lower limbs or, more speculatively, to reduce peripheral arterial perfusion, thereby increasing the flow across the ductus arteriosus or ventricular septal defect to the right side of the circulation. Before the advent of surgical treatment (Fig. 13.45), most patients died well before adult life.

Fig. 13.45 Fallot’s tetralogy. The full features in a classical case are right ventricular hypertrophy, ventricular septal defect, pulmonary hypertension and an overriding aorta. This patient underwent surgical correction as a teenager when pulmonary hypertension was well established. Note the thicknesses of the right and left ventricles are almost equal. An arrow shows a patch that was used to close the ventricular septal defect. This is an old specimen. Nowadays lesions such as these would be corrected within the first year of life.

Another important complex abnormality is transposition of the great arteries. This presents early in life and requires prompt surgery. There are several different forms but in the most important the aorta drains the right ventricle and the pulmonary artery the left. This creates two closed circulations. Post-natal life is only possible if these mix via an atrial or ventricular septal defect or a patent ductus arteriosus. A complete surgical correction is often possible, usually by ‘switching’ the pulmonary artery and aorta at their origin from the heart and re-implanting the coronary arterial ostia. In the best surgical centres excellent results are now obtained, with mortality rates well below 10%.

Congenital valvular abnormalities

The only common congenital abnormality is a bicuspid aortic valve. The vast majority of these are asymptomatic, and the valve is neither incompetent nor stenotic. However, the risk of aortic stenosis in adult life is substantially increased (Fig. 13.29A) and there is a strong association with dissection of the aorta. Small defects (fenestrations) are frequently observed at autopsy, usually in aortic valves, but have no functional significance.

Occasional cases of congenital aortic or pulmonary stenosis do occur. Most tricuspid and mitral abnormalities are part of complex abnormalities rather than isolated lesions.

Coronary arterial abnormalities

There is considerable variation in the normal anatomy of the major coronary vessels and this is usually of no clinical importance. For example, the circumflex branch of the left coronary artery is sometimes small and there is a corresponding increase in the length and distribution of the terminal parts of the right artery. Similarly, the coronary arterial ostia are occasionally malpositioned, but these cause no obvious clinical effects. Many different anomalies have been described. Some are of no clinical importance, while others are associated with an increased risk of sudden death or cardiac disease. For example, one of the coronary arteries may arise from the pulmonary artery, and the myocardium is therefore perfused with deoxygenated blood.

Multisystem diseases

Cardiac changes are often present in association with multisystem disease. In sarcoidosis and rheumatoid disease, for example, granulomatous lesions can develop in the heart, and, if they involve the conduction pathways, arrhythmias or heart block can develop. In some forms of amyloidosis (Ch. 7), the heart is involved. At autopsy, the cardiac muscle has a characteristic glassy brown appearance and, if deposits are extensive, cardiac failure develops. Massive cardiac hypertrophy is a feature of acromegaly, and cardiac failure is the usual cause of death in these patients.

Major cardiac abnormalities are well recognised in both thyrotoxicosis and myxoedema. In severe thyrotoxicosis, the increase in the metabolic rate necessitates an increased cardiac output and peripheral blood flow. Occasionally, this may in itself precipitate ‘high output’ cardiac failure. More frequently, thyrotoxicosis unmasks subclinical coronary or hypertensive heart disease. Atrial fibrillation is particularly common in elderly patients with thyrotoxicosis.

Most patients with myxoedema have an enlarged cardiac outline on chest X-ray. This may be due to left ventricular dilatation or pericardial effusion; these can be distinguished by echocardiography. Characteristically, there is a bradycardia, low voltage ECG and decreased cardiac output. There are usually no specific pathological findings either macroscopically or microscopically. The response to thyroid hormone therapy is often excellent, but angina, and even myocardial infarction, can be precipitated with anything but the smallest doses.

Alcoholism

Cardiac failure is not uncommon in chronic alcoholism. In some cases it can be attributed to common disorders such as coronary artery disease or hypertension. However, in a proportion of patients, no specific cause is determined and ‘alcoholic cardiomyopathy’ is diagnosed. In these patients the macroscopic and microscopic findings are identical to those of other forms of idiopathic cardiomyopathy, and there is some debate as to the exact role of heavy alcohol consumption. Alcohol abuse is associated with an increased risk of sudden death.

Pregnancy

Substantial circulatory changes occur in pregnancy, most notably an increase in circulating blood volume. Cardiac failure may become apparent for the first time during pregnancy, especially in patients with valvular disorders, such as mitral stenosis. Hypertension is one of the cardinal signs of pre-eclampsia but, while cardiac failure and pulmonary oedema can develop in the full syndrome, the disorder is not primarily cardiac in origin (Ch. 19). A characteristic form of cardiomyopathy (discussed below) occasionally develops in the post-partum period.

Iatrogenic disease

Iatrogenic (‘doctor-induced’) cardiac disease is now of some importance because of the increasing use of cytotoxic drugs and of radiotherapy in the treatment of mediastinal tumours. Radiotherapy causes patchy areas of interstitial fibrosis in the myocardium (probably as a result of direct damage to small capillaries) and pericarditis. Some degree of cardiac muscle cell necrosis is a frequent result of treatment with cytotoxic drugs, such as doxorubicin, that interfere with DNA and RNA replication and protein synthesis. This can produce acute cardiac toxicity but may also be associated with an increased long-term incidence of cardiac failure. An increased incidence of heart failure has recently been reported in patients receiving the erb-2 antagonist trastuzumab (Herceptin). It is therefore possible that this agent has a direct cardiotoxic effect.

Dilated (congestive) cardiomyopathy (DSCM)

The incidence of this disorder in Europe and North America is about 35 cases per 100 000 per year. The median age at presentation is about 50 years but young adults may be affected. Typically, the coronary arteries are free of significant atheroma but the ventricles are dilated and hypertrophied (Fig. 13.46). There may be adherent mural thrombi and histological evidence of interstitial fibrosis and hypertrophy of muscle fibres. There is clinical evidence of cardiac disease in the relatives of at least 20% of patients. Current studies are demonstrating an increasing range of mutations. The pattern of inheritance can be autosomal dominant or recessive, X-linked or mitochondrial. These mutations involve genes that code for both cytoskeletal and sarcomeric proteins. A variety of other genetic abnormalities have been detected in young patients with cardiomyopathy. Some relate to fatty acid oxidation, mitochondrial oxidative phosphorylation or the cardiac-specific expression of the dystrophin gene.

Fig. 13.46 Dilated (congestive) cardiomyopathy. There is marked hypertrophy of both the left and right ventricles. Note the adherent mural thrombus at the apex of the left ventricle. No underlying cause was determined in this patient.

Some cases of viral myocarditis appear to progress to dilated cardiomyopathy but there is no firm evidence of viral infection in the majority of cases. The pathological features of chronic alcoholic heart disease and dilated cardiomyopathy are similar. The outlook in dilated cardiomyopathy is poor and only 50–60% of patients survive 2 years. It is essential to investigate these patients in the hope of identifying a treatable disorder such as coronary artery or aortic valve disease. Young patients with dilated cardiomyopathy are often considered for cardiac transplantation.

Hypertrophic (obstructive) cardiomyopathy (HOCM)

This is a common autosomal dominant disorder that is thought to affect 1 in 500 of the population. The clinical, echocardiographic and pathological features in hypertrophic cardiomyopathy are often characteristic (Fig. 13.47). The chief feature is massive left ventricular hypertrophy, usually most marked in the interventricular septum close to the aortic outflow tract. In most cases the disease becomes apparent after the pubertal growth phase or in early adult life. Patients present with a variety of signs or symptoms but atrial fibrillation, ventricular arrhythmias and sudden death are the most important complications. Histological sections of the left ventricle show fibre hypertrophy, interstitial fibrosis and a characteristic disordered arrangement of muscle fibres termed disarray.

Fig. 13.47 Hypertrophic cardiomyopathy. The patient was a 24-year-old male who died suddenly. Note the marked and asymmetrical enlargement of the interventricular septum (asterisk).

Many cases are familial and chromosomal abnormalities can be identified in up to 50% of patients. Mutations have been described in many different cardiac muscle proteins, and in some the exact nature of the amino acid substitution influences the course of the disease. The products of the genes implicated in hypertrophic cardiomyopathy include the structural proteins troponin T and alpha-tropomyosin and cardiac myosin-binding proteins.

Arrhythmogenic right ventricular cardiomyopathy (ARVC)

Although less common than dilated or hypertrophic cardiomyopathy, this is an important disorder with a strong familial tendency. The exact incidence of this disorder is not known, but after hypertrophic cardiomyopathy it is the commonest cause of unexpected cardiac death in a previously fit young person. The characteristic change is progressive loss of right ventricular myocytes with associated fibrosis, inflammation and adipose tissue replacement. In some cases there is clear evidence of septal or left ventricular disease. A small number of gene mutations have been identified, including proteins involved in cell to cell adhesion, such as desmoplakin. Some patients have unusually curled or woolly hair, and peripheral hyperkeratosis.

In the future it is likely that many forms of cardiomyopathy will be classified and treated on the basis of the exact underlying genetic abnormality.

Other cardiomyopathies

Many other forms of cardiomyopathy have been described, usually in specific clinical settings.

Puerperal cardiomyopathy occurs in the last months of pregnancy, or within 6 months of delivery. There is no history of pre-existing cardiac disease and the clinical outcome is variable. In some cases cardiac failure resolves completely, although recurrence in subsequent pregnancies is likely.

In restrictive cardiomyopathy there is restrictive filling and decreased diastolic volume of one or both ventricles. This is caused by myocardial or endocardial disease that stiffens the heart by infiltration or fibrosis. In some cases there is no obvious cause and the disease is termed primary restrictive cardiomyopathy.

Endomyocardial fibrosis is a curious form of myocardial disease found in the tropics, chiefly in Uganda and the Sudan. The cause is unknown, but there is marked fibrosis of the inner parts of the myocardium, and mural thrombi are common. In some patients with severe cardiac failure, there is a prominent persistent peripheral blood eosinophilia and evidence of multiple systemic emboli (Löffler’s endocarditis). This occurs in both tropical Africa and, sporadically, in the West and is usually fatal. The cause is uncertain.

The most important cause of secondary restrictive cardiomyopathy is infiltration of the myocardium by amyloidosis, of either light chain (AL) or transthyretin-related (ATTR) type. Familial forms of cardiac amyloidosis are caused by mutated TTR.