Atherosclerosis46
6.2 Thrombosis48
6.3 Embolism49
Atherosclerosis, a common degenerative disease of arteries characterised by thickening of the intima as a result of deposition of lipids, is a common cause of illness in industrialised countries and is the main pathological process that leads to cardiovascular disease. Infarction can result from atherosclerosis, and also from the intravascular events of thrombosis and embolism.
6.1. Atherosclerosis
Atherosclerosis causes narrowing and/or weakening of arteries, and is the pathological process underlying many common diseases such as myocardial infarction (heart attacks), strokes and aneurysms. It is an acquired, degenerative condition which affects large- and medium-sized arteries, e.g. aorta, carotid and coronary arteries, where it begins in the innermost intimal layer. It is characterised by lipid deposition with consequent inflammation and fibrosis. Atheroma (from the Greek word for porridge that describes the necrotic material in the core of the lesions) is a term which is often used synonymously with atherosclerosis.
Epidemiology and risk factors
Atherosclerosis is common in industrialised countries but less common elsewhere. If individuals from countries with a low incidence migrate to one with a high incidence, their risk of atherosclerosis increases, presumably as a result of adopting a ‘Western’ lifestyle.
The risk factors for atherosclerosis can be divided into those that are non-modifiable (e.g. age, sex) and those that are modifiable as a result of lifestyle changes or drug therapy. Important risk factors are:
• Age. Death rates from the complications of atherosclerosis increase with age.
• Male sex. Premenopausal women have a low rate of death from complications of atherosclerosis; the protective factor is thought to be high oestrogen levels. After the menopause, the incidence of complications increases and by old age it equals that of males.
• Family history. A family history of atherosclerotic-related disease confers an increased risk. This familial predisposition is probably polygenic in most cases, but in some patients there is a specific inherited abnormality of lipid metabolism causing hyperlipidaemia.
• Hyperlipidaemia. The cholesterol in low-density lipoprotein (LDL) is particularly important as a risk factor. The ratio of LDL to high-density lipoprotein (HDL) is also important, since a low LDL/HDL ratio appears to have a protective effect. The mechanism is thought to be related to their functions: LDL delivers lipids to tissues, whereas HDL transports it to the liver for metabolism; therefore, HDL could remove lipids from developing plaques. The LDL/HDL ratio is lowered by exercise, consumption of polyunsaturated fatty acids and moderate amounts of alcohol, whereas it is increased by smoking, obesity and a diet rich in saturated fats. Circulating cholesterol can also be reduced by drugs (the statins).
• Hypertension. Reduction of blood pressure in hypertensive patients reduces the risk of strokes and ischaemic heart disease.
• Cigarette smoking. Tobacco can be atherogenic through damage to endothelial cells by toxins and through the increase in LDL/HDL ratio.
• Diabetes mellitus. This important risk factor could act through hypercholesterolaemia or a direct toxic effect on endothelial cells.
• Physical inactivity. Lack of exercise promotes obesity and increases LDL/HDL ratios.
Pathogenesis
The earliest visible lesion of atherosclerosis is the fatty streak which results from accumulation of lipid-laden macrophages within the intima and which can be seen in the arteries of children. Fatty streaks are flat, pale yellow spots.
Atheromatous plaques occur later in life and contain macrophages intermingled with proliferating smooth muscle cells, capped by fibrous tissue. Lipid, particularly cholesterol, may be present within both macrophages and smooth muscle cells. Angiogenesis (proliferation of small blood vessels) is stimulated at the periphery of the lesions. A mature fibrolipid plaque is composed of:
• a core of necrotic lipid-rich material
• a chronic inflammatory infiltrate containing lymphocytes, macrophages, smooth muscle cells and myofibroblasts surrounding the core
• a fibrous cap
• small blood vessels entering the periphery of the plaque.
These plaques protrude into the vessel lumen and can cause significant narrowing. The underlying arterial wall is weakened by the chronic inflammation.
The response to injury hypothesis
Several different theories have been proposed to explain the initiation and evolution of atherosclerosis. The current favoured idea is the ‘response to injury hypothesis’, which brings some of these theories together. Damage to the arterial endothelium leads to increased permeability of the vessel wall and attachment of platelets and monocytes. The increased permeability allows lipid to enter the vessel wall. Meanwhile, the attached platelets and monocytes produce growth factors which stimulate smooth muscle cells of the arterial media to migrate into the intima and proliferate. One of these growth factors is platelet-derived growth factor (PDGF). This is a locally acting polypeptide which binds to cell surface receptors and triggers a chain of events which may enable genes to switch on and produce proteins which promote cell proliferation. Proliferating smooth muscle cells acquire some fibroblast-like characteristics and produce collagens and proteoglycans, which form the fibrotic cap and matrix of the atherosclerotic plaque. The monocytes transform into macrophages within the intima. These macrophages ingest the lipid that has entered the intima through the leaky endothelium (Figure 15). Macrophages with lipid in their cytoplasm have a foamy appearance and are called foam cells. The macrophages oxidise the lipids they have ingested, and these oxidised lipids have a number of effects that seem to be important in the development of the plaque. In particular, oxidised lipids:
• are chemotactic for circulating monocytes
• inhibit motility of macrophages already in the plaque
• stimulate the macrophages to release growth factors and cytokines which attract inflammatory cells into and around the plaque
• upregulate endothelial cell adhesion molecules, thus promoting adherence of inflammatory cells (see Ch. 9)
• are cytotoxic and cause further endothelial damage.
Lipids and atherosclerosis
Low-density lipoproteins (LDL) are rich in cholesterol and raised blood levels of LDL are an important factor in plaque genesis. Both genetic and environmental dietary factors can determine the LDL levels, but the precise mechanism of this relationship with plaque development is not known. Genetic abnormalities can lead to increased blood levels in very young people, who may suffer heart attacks and strokes in their late teens or early twenties. There is a strong epidemiological correlation between cardiovascular disease and high LDL blood levels. In contrast, there is a reduced risk of atherosclerosis with high levels of high-density lipoproteins (HDL).
Fish oils
Populations which have a high dietary intake of fish oil containing omega-3 fatty acids (a special type of polyunsaturated fatty acid) seem to be protected from developing complicated atherosclerosis. Fish oils may have a lipid-lowering effect in the blood, resulting in reduced levels of LDL and raised levels of HDL. Fish oils may also reduce levels of thromboxane A2, which is metabolised from arachidonic acid in platelets and increases their capacity to aggregate. Reducing thromboxane A2 levels may reduce the risk of thrombosis.
Complications of atherosclerotic plaques
Atherosclerotic plaques are prone to a number of possible complications, namely:
• ulceration and thrombosis
• haemorrhage
• aneurysm
• calcification.
The reason atherosclerosis is a serious condition is that some of the above listed complications can produce potentially fatal diseases. Since the plaque is intimal and protrudes into the lumen of the vessel, haemorrhage or thrombosis can cause narrowing (stenosis) or complete blockage (occlusion) of the artery (Figure 16). If the artery is an end-artery (see Box 5), the tissue supplied by the artery cannot get blood from elsewhere, and it will die, causing infarction. Alternatively, weakening of the wall by the inflammation associated with the atherosclerotic plaque can lead to aneurysm formation.
Box 5
Some tissues receive blood from several different arteries via a collateral circulation. Obstruction of one of these arteries, whether by embolism, thrombosis, atherosclerosis or other cause, is unlikely to cause critical ischaemia because the blood supply can be maintained from the other arteries. However, in some tissues only one artery supplies any particular area, and obstruction of such a vessel is likely to cause an infarct; these arteries are called end-arteries. Organs with end-arteries include the heart and brain.
Haemorrhage
Blood can be forced into the plaque from the lumen of the vessel or bleeding can occur from the vessels vascularising the base and edges of the plaque. The sudden increase in size of the plaque can cause critical ischaemia in the territory supplied by the artery.
Aneurysm formation
The presence of an intimal plaque leads to atrophy and weakening of the underlying media. The weakened vessel wall may dilate and eventually a large sac is formed. This is called an aneurysm (the definition of aneurysm is a permanent abnormal dilatation of an artery). Aneurysms can rupture, with consequent life-threatening haemorrhage. In addition, they commonly contain thrombus, fragments of which can become dislodged and embolise (see Section 6.3 Embolism).
Calcification
Old atherosclerotic plaques often undergo dystrophic calcification. Hence atherosclerotic arteries can sometimes be seen on radiographs. This complication, unlike the three mentioned previously, does not have lethal effects.
6.2. Thrombosis
Thrombosis is the formation of a blood clot within vascular spaces during life, and the resulting clot is called a thrombus. This is in contrast to the term clotting, which can also be applied after death or to blood in a test tube. There are three main predisposing factors for thrombus formation, known as Virchow’s triad:
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