Cardiovascular system

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Chapter 13 Cardiovascular system

Common clinical problems from cardiovascular disease 271
Pathological basis of cardiovascular signs and symptoms 271
Age-related vascular changes 272
Aneurysms 278
Diabetic vascular disease 284
Vasculitis 284
Radiation vascular disease 287
Complications in vessels used as arterial bypasses 289
Tumours of blood vessels 289

Normal structure and function of the heart 290
Sudden cardiac death 297
Pericarditis and myocarditis 307

Congenital cardiovascular disease 308

Unusual cardiac diseases 312

Newly described forms of cardiac disease
Tumours of the heart and pericardium 315
Commonly confused conditions and entities relating to cardiovascular pathology 316



Pathological basis of cardiovascular signs and symptoms

Sign or symptom Pathological basis
Angina Myocardial ischaemia due to spasm, atheroma or thrombosis of coronary arteries
Abnormal blood pressure

Either ‘essential’ (primary, idiopathic) due to as yet undefined genetic and environmental factors, or secondary to a disease resulting in increased levels of hormones with hypertensive effects


Reduction of actual or effective circulating blood volumeAbnormal heart sounds


Turbulence of blood flow through stenotic or incompetent valves

Friction rub


Indistinct sounds

Pericardial effusionAbnormal ECG

Altered waveform

Disturbed myocardial depolarisation/ repolarisation commonly due to ischaemia or infarction

Altered rhythm

Disturbed conduction of electrical activity due to, for example, disease affecting conducting tissue or causing appearance of foci of ectopic electrical activityAbnormal pulseDisordered heart rhythm or arterial flowRaised jugular venous pressureIncreased central venous pressure due to right or congestive cardiac failureOedemaIf due to vascular disease, attributable to raised venous pressure (e.g. in cardiac failure or venous thrombosis) exceeding plasma oncotic pressureDyspnoeaPulmonary oedema due to left ventricular failure or mitral stenosisCyanosisPartial bypass of pulmonary circulation or acquired impairment of circulation or oxygenationRaised serum troponin or creatinine phosphokinaseRelease of cardiac enzymes into blood due to myocardial infarctionJoint painsSynovial inflammation in rheumatic feverSkin lesions

Leg ulcers

Impaired arterial or venous flow


Interruption of arterial supply

Splinter haemorrhages (under nails)

Microemboli from infective endocarditis

Purpuric rash

Microhaemorrhages in skin due to vasculitisHemiplegiaCerebral haemorrhage or cerebral artery occlusion by thrombus or embolusVisual impairmentCranial (giant cell) arteritis Hypertensive retinopathySudden collapseVaso-vagal syncope Severe dysrhythmia (e.g. ventricular fibrillation) due to myocardial infarction


Cardiovascular disorders are now the leading cause of death in most Western societies (Ch. 2). In England and Wales ischaemic heart disease currently accounts for 27%, and cerebral vascular disorders for 13%, of all deaths. Atherosclerosis is the commonest and most important vascular disease, but many other vascular disorders are recognised.

Normal arterial structure

In all parts of the arterial system, three anatomical layers can be distinguished. The innermost, the intima, is composed of a single layer of endothelium with a thin supporting framework of connective tissue. The internal elastic lamina separates the intima from the middle layer, the media (Fig. 13.1). The aortic media is particularly rich in elastic tissue, but in most medium-sized arteries, such as the coronary arteries, smooth muscle predominates. The outermost layer, the adventitia, is fibrous connective tissue. Small blood vessels, the vasa vasorum, enter from the adventitial aspect and supply much of the media. The intima and innermost media receive nutrients by direct diffusion from the vascular lumen.


Fig. 13.1 Structure of blood vessels. image Muscular artery from a young child. The intima is extremely thin. image Renal vein from a 72-year-old man. Elastic lamellae are indistinct and there is some intimal fibrosis (red coloration). The underlying muscle bundles (pale yellow) are not arranged as regularly as in arteries.


A variety of ageing changes occur in the aorta, arteries and arterioles. Although there is considerable individual variation, changes are usually inconsequential before 40 and most common after 70 years of age. The most important changes are:

progressive fibrous thickening of the intima
fibrosis and scarring of the muscular or elastic media
the accumulation of mucopolysaccharide-rich ground substance
fragmentation of the elastic laminae.

The net effect of these changes is to reduce both the strength and the elasticity of the vessel wall. Progressive dilatation is a common ageing phenomenon in both the aorta and the coronary arteries. In the ascending aorta this can lead to stretching of the aortic valve ring and aortic incompetence. Dilatation of the arch and thoracic aorta produces the characteristic ‘unfolding’ seen in chest X-rays (Fig. 13.2).


Fig. 13.2 Unfolding of the aorta. image There is a prominent bulge (arrow) caused by dilatation of the arch and descending aorta. If the dilatation involves the aortic valve ring, aortic incompetence may result. image Normal X-ray for comparison.

The age-related changes that occur in muscular arteries are usually termed arteriosclerosis. Even arterioles can be affected. Characteristic alterations include smooth muscle hypertrophy and the apparent reduplication of the internal elastic laminae by extra layers of collagen. There is often marked intimal fibrosis and this further reduces the diameter of the vessel. Arteriosclerosis contributes to the high frequency of cardiac, cerebral, colonic and renal ischaemia in the elderly population. The clinical effects become most apparent when the cardiovascular system is further stressed by haemorrhage, major surgery, infection or shock.


image Affects large and medium-sized arteries
image Lesions comprise fatty streaks, fibrolipid plaques and complicated lesions
image Risk factors include increasing age, male gender, hypertension, smoking and diabetes
image Associated with increased levels of low-density lipoprotein (LDL) cholesterol, Lp(a), fibrinogen and factor VII, and reduced levels of high-density lipoprotein (HDL) cholesterol
image Major cause of organ ischaemia (e.g. myocardial infarction)

Atherosclerosis is a disease characterised by formation of focal elevated lesions in the intima of large (aorta) and medium-sized arteries (such as coronary arteries)—termed atherosclerotic plaques. Plaques alone are usually benign asymptomatic lesions, even when they are present in large numbers throughout the arterial tree, but life-threatening ischaemic damage of vital organs may occur when an occlusive thrombosis forms on a spontaneously disrupted plaque (atherothrombosis). Such acute obstructions can occur in many different arteries, resulting in a wide range of clinical disorders (Fig. 13.3). The frequency of atherothrombotic complications has increased drastically during the past 50 years, and the condition is now also common in parts of the Middle and Far East, particularly in those countries where a ‘Western style’ of living has been adopted. Coronary atherothrombosis—‘coronary heart disease’—is one of the commonest causes of death in many societies.


Fig. 13.3 The complications of atherosclerosis.

Atherosclerotic lesions

The formation of lesions starts in young children, especially in societies with a high dietary fat intake. The earliest significant lesion is called a fatty streak. It is a yellow linear elevation of the intimal lining and is composed of masses of lipid-laden macrophages. These fatty streaks have no clinical significance. They may disappear from the arterial intima, but in patients at risk they progress to atherosclerotic plaques (Fig. 13.4). The fully developed plaque is a lesion with a central lipid core with a cap of fibrous tissue covered by the arterial endothelium (Fig. 13.5). Connective tissues in the cap, mainly collagens, provide the structural strength of the plaque and are produced by smooth muscle cells (SMCs). Inflammatory cells, including macrophages, T-lymphocytes and mast cells, reside in the fibrous cap. They are recruited from the arterial endothelium or, in advanced plaques only, from newly formed microvessels present at the base of, or around, the atheroma.


Fig. 13.4 Lesions of atherosclerosis. image Early aortic atherosclerosis. Note the many small fatty streaks. Some larger dot-like lesions are also present. These are common lesions in all racial groups and both genders. image Advanced complicated atherosclerosis in the abdominal aorta. Many of the lesions have ruptured and become thrombosed.


Fig. 13.5 Atheromatous plaque. image Diagram of an atheromatous plaque. Some of the features can be seen in the photomicrograph image from the coronary artery of a 72-year-old.

The atheroma is rich in cellular lipids and cellular debris derived from macrophages that have died inside the plaque. It is soft (semi-fluid), highly thrombogenic and often bordered by a rim of so-called foam cells. The foam cell results from uptake of oxidised lipoproteins via a specialised membrane-bound scavenger receptor. This is one of the most distinctive pathological processes in plaque formation. Dystrophic calcification of the plaque can be extensive and occurs late in the process of plaque development. It may serve as a marker for atherosclerotic vessel disease in angiograms or in CT images. Plaques have a tendency to form at arterial branching points and bifurcations. This illustrates the important role of turbulent blood flow in the pathogenesis of atherosclerosis. In the late stages many individual lesions may become confluent and cover large parts of arteries (Fig. 13.4B).

What causes atherosclerosis?

Hypercholesterolaemia is by far the most important risk factor for atherosclerosis. It can cause plaque formation and growth in the absence of other known risk factors. It has been suggested that if plasma cholesterol levels in a population were below 2.5 mmol/l (such as in the traditional Chinese culture), symptomatic atherosclerotic disease would be almost non-existent. The most compelling evidence for the importance of LDL cholesterol comes from studies of patients and animals that have a genetically determined lack of cell membrane receptors for LDL (Fig. 13.6). About 1 in 500 Caucasians is heterozygous for this type of mutation, and has reduced numbers of functional receptors on their cell surfaces and elevated plasma LDL-cholesterol levels (over 8 mmol/l). Such individuals often develop coronary heart disease in their forties or fifties. The rare patients who are homozygous for one of these mutations (approximately 1 per million) have much higher cholesterol levels and usually die from coronary atheroma in infancy or the teens.


Fig. 13.6 Major pathways of lipoprotein metabolism. This is a much simplified outline of lipid metabolism. Note that LDL uptake in peripheral tissues is receptor-mediated. HDL apoprotein accepts cholesterol from tissues. This can then be absorbed by specific receptors in the liver (reverse cholesterol transport) or recycled into LDL. (HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.)

The importance of other risk factors beyond hypercholesterolaemia is illustrated by the huge variation in expression of severity of disease among groups of patients with the same cholesterol levels. Major risk factors are smoking, hypertension, diabetes, male gender and increasing age. They appear to accelerate the process of plaque formation driven by lipids. Less strong risk factors include obesity, a sedentary lifestyle, low socio-economic status and low birth weight. At present there is also increasing interest in the role of micro-organisms in the evolution of atherosclerotic disease. The cumulative effect of several, often innocent or subclinical, infections with common bacteria such as Chlamydia pneumoniae, cytomegalovirus, influenza and dental pathogens are thought to increase the risk of atherosclerosis by switching on evolutionarily conserved pathways of inflammation. There is also recent evidence that high-fat diets and obesity may promote translocation of commensal-derived endotoxin from the gut into the general circulation and there induce inflammation, insulin resistance and atherosclerosis.

How do lesions develop?

Generally, the development of atherosclerosis is a two-step process. The first step is injury to the endothelium of the arterial wall and the second is a tissue response of the vascular wall to the injurious agents. Chronic or episodic exposure of the arterial wall to these processes leads over many years to formation of plaques. This concept, initially introduced by Ross and Glomset in 1972, is now convincingly supported by carefully designed postmortem studies of patients of different ages and racial origin and from studies in animals that develop atherosclerosis either spontaneously or following high-fat or cholesterol-supplemented diets.

Injured endothelial cells at sites of lesion formation undergo profound functional alterations which include an enhanced expression of cell adhesion molecules, including ICAM-1 and E-selectin, a high permeability for macromolecules such as LDL, and increased thrombogenicity. This allows inflammatory cells and lipids to enter the intimal layer and form plaques. In more advanced stages of plaque formation large amounts of macrophages and T-cells accumulate in the plaque tissue. Lipid-laden macrophages (foam cells) die through apoptosis, spilling their lipid into an ever-enlarging lipid core. In this respect the response to injury in atherosclerosis has all the features of a chronic inflammatory process.

As in all chronic inflammatory diseases the inflammatory reaction is followed by a process of tissue repair. Growth factors, particularly platelet-derived growth factor (PDGF), stimulate the proliferation of intimal smooth muscle cells (myointimal cells) and the subsequent synthesis of collagen, elastin and mucopolysaccharide by smooth muscle cells. A fibrous cap encloses the lipid-rich core (Fig. 13.5). Growth factors are secreted by platelets, injured endothelium, macrophages and smooth muscle cells themselves.

Another important mechanism of plaque growth is initiated by small areas of endothelial loss, especially in fully developed plaques. Microthrombi are formed at the denuded areas of the plaque surface. These become organised by the same repair process of smooth muscle cell invasion and collagen deposition. Repeated cycles of this process gradually increase the plaque volume.

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.

1. Progressive lumen narrowing due to high-grade plaque stenosis. Stenosis of more than 50–75% of the vessel lumen leads to critical reduction of blood flow in the distal arterial bed. Consequently, reversible tissue ischaemia develops, especially during effort. Examples are stable angina pectoris (stenosed coronary artery) or intermittent claudication (iliac, femoral or popliteal artery stenosis). When the stenosis is severe, ischaemic pain may also occur at rest. Moreover, longstanding tissue ischaemia may also lead to atrophy of an affected organ, for example renal atrophy in cases of atherosclerotic renal artery stenosis.
2. Acute atherothrombotic occlusion. Major complications of atherosclerosis are acute events that are initiated by rupture of an atherosclerotic plaque. Plaque rupture exposes highly thrombogenic plaque components (collagen, lipid debris) to the blood stream which leads to activation of the coagulation cascade and thrombotic occlusion of the vessel lumen in a (very) short period of time. Total occlusion leads to irreversible ischaemia causing necrosis (infarction) of the tissues supplied by the obstructed artery. Examples are myocardial infarction (coronary arteries), stroke (carotid or cerebral arteries) and lower limb gangrene (iliac, femoral or popliteal arteries).
3. Embolisation of the distal arterial bed. Another complication that may arise from atherothrombosis is detachment of small thrombus fragments. These then embolise the arterial bed distal to the ruptured plaque. Embolic occlusion of small vessels may cause small infarctions in organs. In the heart this can be dangerous, since small foci of necrosis can also serve as a substrate for dangerous arrhythmias. In cases of large ulcerating plaques of the aorta, small soft (lipid-rich) parts of plaques can lodge in small distal vessels of kidney, leg or skin (cholesterol emboli). Embolisation of carotid arterial atheromatous debris is a common cause of stroke.
4. Ruptured abdominal atherosclerotic aneurysm. The media beneath atherosclerotic plaques gradually weaken, probably due to the lipid-related inflammatory activity in the plaque. This causes gradual dilatation of the vessel. This is a slow but progressive process, and hence a disease of the elderly. This process is often asymptomatic. Sudden rupture causes massive retroperitoneal haemorrhage with a high mortality. Aneurysms of more than 5 cm in diameter have a high risk of rupture. In addition, thrombus detached from the inner surface of aneurysms is a source of embolisation in the legs.

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.

Preventive and therapeutic approaches to atherosclerosis and atherothrombosis

Smoking cessation, control of blood pressure, weight reduction, regular exercise and dietary modifications are all of benefit and are now widely promoted. In Mediterranean communities, a much lower proportion of energy is obtained from saturated fat, and coronary heart disease death rates are much lower. Diets rich in polyunsaturated fat are associated with low coronary heart disease rates. This is the logic behind the advice that we should all eat five portions of fruit or vegetables each day. Fatty acids found in fish have cardioprotective effects. The American Heart Association now recommends at least two servings of fish, especially oily fish, per week.

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.


image Localised, permanent, abnormal dilatation of a blood vessel
image Atherosclerotic. Usually occur in the abdominal aorta; rupture causes retroperitoneal haemorrhage
image Dissecting. Usually occur in the thoracic aorta; dissection along the media causes vascular occlusion and haemopericardium
image Berry. Occur in the circle of Willis; rupture causes subarachnoid haemorrhage
image Capillary micro-aneurysms. May be intracerebral (in hypertension), causing cerebral haemorrhage, or retinal (in diabetes), causing diabetic retinopathy
image Syphilitic. Usually occur in the thoracic area
image Mycotic. Rather rare; commonest in the cerebral arteries

An aneurysm is a localised permanent dilatation of part of the vascular tree. Permanent dilatation implies that the vessel wall has been weakened. In contrast, a false aneurysm is a blood-filled space that forms around a blood vessel, usually after traumatic rupture or a perforating injury. A haematoma forms and is contained by the adventitial fibrous tissue. A common cause of false aneurysm formation is femoral artery puncture during arteriography or percutaneous angioplasty. The clinical and pathological features of aneurysms are summarised in Table 13.1.

Table 13.1 Clinical effects of aneurysms

Type of aneurysm Site Clinical effects
Atherosclerotic Lower abdominal aorta and iliac arteries
Pulsatile abdominal mass
Lower limb ischaemia
Rupture, with massive retroperitoneal haemorrhage

Aortic dissectionAorta and major branches

Loss of peripheral pulses (e.g. radials)
External rupture (retroperitoneal haemorrhage)
Re-entry from dissected media to lumen causing ‘double-barrelled’ aorta

BerryCircle of WillisSubarachnoid haemorrhageMicro-aneurysms (Charcot–Bouchard)Intracerebral capillariesIntracerebral haemorrhage, associated with hypertensionSyphiliticAscending and arch of aortaAortic incompetenceMycotic (infective)

Root of aorta (direct extension from aortic valve endocarditis)
Any vessel

Thrombosis or rupture, causing cerebral infarction or haemorrhage

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. image 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. image 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.


image Classified aetiologically into essential (primary) hypertension, in which there is no evident cause, and secondary hypertension
image Secondary hypertension may be due to renal disease, adrenal cortical and medullary tumours, aortic coarctation or steroid therapy
image Further classified dynamically into benign hypertension, in which there is gradual organ damage, and malignant hypertension, in which there is severe and often acute renal, retinal and cerebral damage



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:

mild when the diastolic pressure is between 95 and 104 mmHg
moderate at 105–114 mmHg
severe at pressure above 115 mmHg.

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.


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.

Aetiological classification

Hypertension can be classified aetiologically according to whether the cause is unknown—essential (primary or idiopathic) hypertension—or is known—secondary hypertension. Most cases of hypertension are classified as ‘essential’, but the possibility of an underlying cause should always be considered.

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).

Detailed clinical and physiological investigations in patients with essential hypertension indicate that it is not a single entity, and that several different mechanisms may be responsible. The key feature in all patients with established hypertension is an increase in total peripheral vascular resistance.

Table 13.2 Pathogenesis of systemic hypertension

Aetiological classification Causes
Essential (primary) hypertension Unknown, but probably multifactorial involving:

Genetic susceptibility
Excessive sympathetic nervous system activity
Abnormalities of Na/K membrane transport
High salt intake
Abnormalities in renin– angiotensin–aldosterone system

Secondary hypertensionRenal disease

Chronic renal failure
Renal artery stenosis

Endocrine causes

Adrenal tumours (cortical or medullary)
Cushing’s syndrome

Coarctation of aorta Drugs, e.g. corticosteroids, oral contraceptives

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:

the activity of the sympathetic nervous system and the renin–angiotensin–aldosterone system
genetic factors that control vascular tone and influence the reabsorption of sodium in the kidney
the absolute numbers of functional nephrons
low-grade renal damage due to hypertension or inflammation
the rate of renal medullary blood flow
dietary intakes of sodium and potassium.

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.

Secondary hypertension

Hypertension may result from several underlying conditions:

renal hypertension
endocrine causes
coarctation of the aorta
drug therapy.

Renal hypertension

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

renin-dependent hypertension
salt and water overload.

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.

Pathological classification

Hypertension is classified also according to the clinicopathological consequences of the blood pressure elevation. Benign or essential hypertension is often asymptomatic and discovered only during a routine medical examination. Malignant hypertension is a serious condition necessitating prompt treatment to minimise organ damage or the risk of sudden death from cerebral haemorrhage.

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:

cardiac failure with left ventricular hypertrophy and dilatation
blurred vision due to papilloedema and retinal haemorrhages
haematuria and renal failure due to fibrinoid necrosis of glomeruli
severe headache and cerebral haemorrhage.

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

Cause Pathophysiology
Acute or chronic left ventricular failure Raised left ventricular pressure → raised venous pressure
Mitral stenosis Raised left atrial pressure → raised pulmonary venous pressure
Chronic bronchitis and emphysema Hypoxia → pulmonary vasoconstriction → raised pulmonary venous pressure
Emphysema Loss of pulmonary tissue → reduced vascular bed
Recurrent pulmonary emboli Reduction in pulmonary vascular bed available for perfusion
Primary pulmonary hypertension Cause of raised pulmonary pressure unknown

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.

Vascular and systemic effects

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.


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.


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.


image Lesions include premature atherosclerosis, and microangiopathy causing damage to kidneys, nerves and retina
image Complications include gangrene, renal failure and blindness
image Effective control of diabetes reduces the incidence of renal and retinal disease

Patients with diabetes, particularly juvenile-onset insulin-dependent diabetes, may develop three forms of vascular disease.


Both males and females develop premature, and sometimes severe, atherosclerosis. Even diabetic pre-menopausal females can develop substantial atheroma.

Hypertensive vascular disease

This is a frequent complication, especially when there is diabetic renal disease (Ch. 21).

Capillary microangiopathy

This is the most important and characteristic change in diabetes. The alterations are found throughout the systemic circulation and can be viewed directly in the retina (Fig. 13.13). Small arterioles and capillaries are affected and the principal clinical effects are diabetic retinopathy, diabetic glomerulosclerosis and peripheral neuropathy. The biochemical changes are complex and include abnormal glycosylation of proteins within the vessel wall. Although thickened, the basement membranes are unusually permeable, and there is increased passive transudation of protein. Small vessels dilate, forming capillary micro-aneurysms. In the eye, protein leakage stimulates a fibrous and vascular response, which damages the complex neural network of the retina. Capillary thrombosis causes retinal ischaemia. This is a stimulus to the ingrowth of new capillaries, which causes further retinal damage. Some degree of diabetic retinal disease is inevitable in longstanding diabetes, but only a minority of patients become blind. Intimal thickening of renal arterioles and micro-aneurysm formation in the glomerular capillaries are the underlying causes of diabetic renal disease. The excretion of small amounts of protein in the urine (micro-albuminuria) is the first evidence of this. Peripheral neuropathy results from disease of small vessels supplying nerves. Multicentre trials have shown that the rate of progression of major complications such as diabetic retinopathy and nephropathy can be reduced by careful control of blood sugar levels and prompt treatment of hypertension.


Fig. 13.13 Fluorescein angiogram of the eye of a diabetic patient. Note the numerous, small, dot-like capillary micro-aneurysms.


image Multisystem disorders but with a predilection for highly vascular tissues such as skin, renal glomerulus, upper respiratory and gastrointestinal tract
image Now classified according to the size of vessel affected, i.e. small, medium and large vessel vasculitis
image Exact mechanisms uncertain but include disordered immunity with complement activation and in some cases immune complex deposition. Auto-antibodies may be present



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.

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