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

Ultimately it is the kidneys that are responsible for the control of blood volume and blood pressure, largely through the handling of sodium in the renal tubules. Factors that influence this include:

Secondary hypertension

Hypertension may result from several underlying conditions:

Benign (essential) hypertension

The increased peripheral vascular resistance and cardiac workload associated with hypertension produce left ventricular hypertrophy. During life this can be detected electrocardiographically, and at postmortem there is often substantial concentric thickening of the left ventricle. With the development of congestive cardiac failure, the hypertrophy can be obscured by left ventricular dilatation. Some patients with hypertension also have coronary arterial atherosclerosis and evidence of consequent ischaemic heart disease.

Longstanding hypertension produces generalised disease of arterioles and small arteries, in addition to enhancing the development of atherosclerosis. The changes are most easily appreciated in the retina during life, and in the kidneys at autopsy. Medium-sized renal arteries and renal arterioles show marked intimal proliferation and hyalinisation of the muscular media. This produces focal areas of ischaemia with scarring, loss of tubules and periglomerular fibrosis. The cortical surfaces are finely granular.

Malignant hypertension

Malignant hypertension is a clinical and pathological syndrome. The characteristic features are a markedly raised diastolic blood pressure, usually over 130–140 mmHg, and progressive renal disease. Renal vascular changes are prominent, and there is usually evidence of acute haemorrhage and papilloedema (Fig. 13.11). Malignant hypertension can occur in previously fit individuals, often black males in their third or fourth decade. However, most cases occur in patients with evidence of previous benign hypertension; this is sometimes termed accelerated hypertension.

Fig. 13.11 Hypertensive fundus. Ocular fundus from a patient with hypertension. The outline of the blood vessels is caused by the reflection of light from the column of blood (the light reflex). Because the wall of the arteriole is thickened in hypertension, the lumen of the vessel is narrowed and the light reflex is reduced (between the arrows).

The consequences of malignant hypertension are:

The characteristic histological lesion of malignant hypertension is fibrinoid necrosis of small arteries and arterioles (Fig. 13.12). The kidney is frequently affected and some degree of renal dysfunction is inevitable. Occasionally there is massive proteinuria, and renal failure develops. Acute left ventricular failure can occur.

Fig. 13.12 Malignant hypertension. There is fibrinoid necrosis (red) in the wall of a medium-sized renal artery. Glomeruli are below and to the right of this artery.

Pulmonary hypertension

The pathophysiological mechanisms associated with pulmonary hypertension are summarised in Table 13.3.

Table 13.3 Pathological causes and physiological changes in pulmonary hypertension

When pulmonary hypertension develops rapidly (following acute left ventricular failure, for example), there is massive transudation of fluid from the pulmonary capillaries into the pulmonary interstitial space and alveoli. This causes the characteristic clinical picture of acute and distressing shortness of breath and expectoration of lightly bloodstained, watery fluid. In chronic pulmonary hypertension, the pulmonary arteries develop a progressive series of reactive changes. These include muscular hypertrophy, intimal fibrosis and dilatation. There are repeated episodes of haemorrhage into the alveolar spaces, which contain haemosiderin (iron pigment)-laden macrophages.

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.

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