Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease’s aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.
Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in the large arteries. The anatomy of a normal artery is shown in Fig. 1. The early lesions of atherosclerosis consist of subendothelial accumulations of cholesterol-engorged macrophages, called ‘foam cells’. In humans, such ‘fatty streak’ lesions can usually be found in the aorta in the first decade of life, the coronary arteries in the second decade, and the cerebral arteries in the third or fourth decades. Because of differences in blood flow dynamics, there are preferred sites of lesion formation within the arteries. Fatty streaks are not clinically significant, but they are the precursors of more advanced lesions characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells (SMCs). Such ‘fibrous lesions’ typically have a ‘fibrous cap’ consisting of SMCs and extracellular matrix that encloses a lipid-rich ‘necrotic core’. Plaques can become increasingly complex, with calcification, ulceration at the luminal surface, and haemorrhage from small vessels that grow into the lesion from the media of the blood vessel wall. Although advanced lesions can grow sufficiently large to block blood flow, the most important clinical complication is an acute occlusion due to the formation of a thrombus or blood clot, resulting in myocardial infarction or stroke. Usually, the thrombosis is associated with rupture or erosion of the lesion.
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