Chapter 13 Cardiovascular system
COMMON CLINICAL PROBLEMS FROM CARDIOVASCULAR DISEASE
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 volume | |
Abnormal heart sounds | |
Turbulence of blood flow through stenotic or incompetent valves | |
Pericarditis | |
Pericardial effusion | |
Abnormal ECG | |
Disturbed myocardial depolarisation/ repolarisation commonly due to ischaemia or infarction | |
Disturbed conduction of electrical activity due to, for example, disease affecting conducting tissue or causing appearance of foci of ectopic electrical activity | |
Abnormal pulse | Disordered heart rhythm or arterial flow |
Raised jugular venous pressure | Increased central venous pressure due to right or congestive cardiac failure |
Oedema | If due to vascular disease, attributable to raised venous pressure (e.g. in cardiac failure or venous thrombosis) exceeding plasma oncotic pressure |
Dyspnoea | Pulmonary oedema due to left ventricular failure or mitral stenosis |
Cyanosis | Partial bypass of pulmonary circulation or acquired impairment of circulation or oxygenation |
Raised serum troponin or creatinine phosphokinase | Release of cardiac enzymes into blood due to myocardial infarction |
Joint pains | Synovial inflammation in rheumatic fever |
Skin lesions | |
Impaired arterial or venous flow | |
Interruption of arterial supply | |
Microemboli from infective endocarditis | |
Microhaemorrhages in skin due to vasculitis | |
Hemiplegia | Cerebral haemorrhage or cerebral artery occlusion by thrombus or embolus |
Visual impairment | Cranial (giant cell) arteritis Hypertensive retinopathy |
Sudden collapse | Vaso-vagal syncope Severe dysrhythmia (e.g. ventricular fibrillation) due to myocardial infarction |
DISEASES OF THE ARTERIES AND OTHER VESSELS
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.
AGE-RELATED VASCULAR CHANGES
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).
ATHEROSCLEROSIS
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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.
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.
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.
How do lesions develop?
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.
Clinical manifestations of atherosclerosis
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.
Preventive and therapeutic approaches to atherosclerosis and atherothrombosis
Secondary prevention of atherosclerotic complications
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.
ANEURYSMS
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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 | |
Aortic dissection | Aorta and major branches | |
Berry | Circle of Willis | Subarachnoid haemorrhage |
Micro-aneurysms (Charcot–Bouchard) | Intracerebral capillaries | Intracerebral haemorrhage, associated with hypertension |
Syphilitic | Ascending and arch of aorta | Aortic incompetence |
Mycotic (infective) | 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.
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.
‘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.
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.
HYPERTENSION
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Definition
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.
Aetiological classification
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
Aetiological classification | Causes |
---|---|
Essential (primary) hypertension | Unknown, but probably multifactorial involving: |
Secondary hypertension | Renal disease Endocrine causes |
Coarctation of aorta | |
Drugs, e.g. corticosteroids, oral contraceptives |
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.
Secondary hypertension
Hypertension may result from several underlying conditions:
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).
Pathological classification
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.
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.
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 |
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).
DIABETIC VASCULAR DISEASE
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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.
VASCULITIS
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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.
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