Definition of atherosclerosis

Atherosclerosis is a slowly progressing, pathological process involving the intima and media of large- and medium-sized arteries and leads to the formation of focal lesions (plaques) containing lipid material and fibrous tissue (see Figure 1) [Ross, 1999]. The focal thickenings of the arterial wall or plaques do not usually interfere with arterial flow in the early stage of atherogenesis. When thrombosis is superimposed on non-stenotic lesions, however, blood flow impairment is produced, potentially leading to ischaemia of target organs and tissues.

Figure 1. Formation of an advanced complicated lesion of atherosclerosis.

The arterial lesions

Where do arterial lesions form?
The intima-media thickness, even at birth, differs in different arterial segments, even within the same artery; there are arterial sites, for example, at arterial bifurcations, where focal and eccentric (crescent-like) thickening of the arterial wall occurs, while in other arterial segments (such as main coronary branches) a pattern of diffuse thickening is consistently observed [Stary, 2000]. Both eccentric and diffuse thickening do not represent arterial abnormalities, but rather sites that are more prone to the development of atherosclerotic lesions.

• Epidemiological studies in vivo using high-resolution ultrasound have provided information on the prevalence, extent and severity of atherosclerosis.
• Noninvasive carotid artery end points, such as intima-media thickness, predict the clinical atherosclerotic status (ie, coronary heart disease [CHD] and stroke) [O'Leary, 1999].
• B-mode ultrasound imaging has also been used to evaluate prospectively the natural history of peripheral atherosclerosis evolution by monitoring lesion growth over time [Mercuri, 1996], and its stabilisation in selected groups of patients. This method allows the quantitative measurement of an end point that is closely related to the underlying disease (ie, focal intima-media thickening) [Mercuri, 1996].

A current classification [Stary, 2000; Fuster, 1996] of different types of lesion observed in relation to atherosclerosis is shown in Figure 2.

Figure 2. Types of atherosclerotic lesions.

Foam cells
Foam cells reflect the accumulation of small amounts of lipids, which are exclusively located intracellularly. Gross pathological examination does not allow the detection of foam cells, but they can be visualised using lipophilic stains such as Sudan IV (containing scarlet red as the lipid stain). Occur in early years of life.

Fatty streaks
Fatty streaks are formed from multiple layers of lipid-containing cells, mainly macrophages, but to a lesser extent, smooth muscle cells (see Figure 3). In this type of lesion, lipid material can also be found extracellularly, as a consequence of necrosis of lipid-laden foam cells. Occur in early years of life.

Preatheroma
The preatheroma is a transition lesion deriving from the fatty streak and occurring before a typical atheroma develops. A distinctive feature of preatheroma is the massive accumulation of extracellular lipid material, which breaks the continuity of the smooth muscle cells. While these lesions are associated with marked thickening of the arterial wall, they nevertheless do not interfere with blood flow.

Atheroma
Atheroma is the typical atherosclerotic lesion, caused by the formation of a large lipid core that is derived from the coalescence of extracellular lipid, which results from macrophage necrosis. The lipid core of an atheroma contains some isolated smooth muscle cells, but macrophages are usually located in the periphery of the lipid material. Generally found after puberty.

Fibroatheroma
The distinctive feature of a more advanced lesion, fibroatheroma is the presence of a fibrous cap, which covers the lesion on its luminal side. The fibrous cap results from smooth muscle cells within a dense extracellular matrix, containing collagen and capillaries. Microscopic haemorrhages are occasionally detected in the areas of neovascularisation. Detected in third decade.

Complicated lesions
The fibroatheroma undergoes progressive growth and represents an unstable lesion, which can be complicated by fibrous cap erosions or rupture, intra-plaque haemorrhage or superimposed thrombosis. At this stage, arterial lesions may become associated with ischaemic signs and symptoms owing to significant impairment of blood flow. Complicated lesions are responsible for severe ischaemic syndromes that are associated with atherosclerosis (eg, myocardial infarction and angina pectoris, stroke and transitory ischaemic attacks, obliterating arterial disease of the lower limbs).

Figure 3. Fatty streak formation in atherosclerosis.

Issues

Do microorganisms contribute to the development of atherosclerotic lesions? Infectious microorganisms (Herpes viruses, Chlamydia pneumoniae) have been demonstrated at the level of arterial lesions [Ross, 1999] and high titres of antibodies against these agents have been proposed as prognostic markers for those who have survived a myocardial infarction. There is no definitive proof, however, that these microorganisms contribute to the development of atherosclerotic lesions. Herpes viruses and C. pneumoniae are commonly found in several human organs and tissues, in addition to arteries. Furthermore, when they are injected in experimental animals they fail to produce atherosclerotic lesions.

Rick factors involved in atherosclerosis
Dyslipidaemia Diabetes Nutrition Exercise	Hypertension Smoking Obesity Homocysteine

Are chronic inflammatory processes involved in atherosclerosis?
For several years it has been suggested that atherosclerosis shares several features with chronic inflammatory processes:

• In general, the inflammatory response of an individual tissue to inflammatory stimuli differs with regard to cell types involved in the response, local blood and lymph circulation and the offending agent.
• The inflammatory response of the arterial wall is, to a large extent, unique and quite different from that occurring in other organs or tissues, such as the liver, kidneys, the lung or joints.
• Granulocytes are uncommon in atherosclerotic lesions, while the cells mainly involved in atherogenesis are the macrophages (derived from the circulating monocytes) and T lymphocytes.
• Activated macrophages express antigens, recognised by T lymphocytes, which are in turn stimulated to produce cytokines, acting as amplifiers of the inflammatory process.
• The cell response to repetitive endothelial damage delimits the area of damage through a proliferative reaction.

When the inflammatory process is extensive and maintained over a long period of time, there is an increase of circulating levels of inflammatory markers, such as fibrinogen, C-reactive protein and cytokines.

What causes impaired arterial reactivity?

• Impaired arterial reactivity is caused by abnormalities in the production, release or action of endogenous vasoactive substances, which are normally produced by endothelial cells (eg, nitric oxide, prostacyclin, endothelins).
• In patients with dyslipidaemia, there is evidence of impaired vasodilation in response to a variety of stimuli; to some extent this can be explained by a defect in endothelium-dependent relaxation owing to abnormalities in the arginine-dependent pathway leading to release of nitric oxide or some related compound.

• There is no definite explanation of the mechanism that leads to abnormal endothelium-dependent relaxation. Impaired nitric oxide production release by endothelial cells, and/or enhanced inactivation of endogenous vasodilator(s), have both been proposed as explanations for the abnormality in arterial vasomotion associated with dyslipidaemia [de Divitiis, 1999].
• While in recent years attention has been mainly focused on the arginine-nitric oxide pathway, it should also be mentioned that endothelial cells release other vasoactive substances, such as prostacyclin, endothelium-derived hyperpolarising factor and endothelins.
• These are all potentially involved in the abnormalities of vasodilation associated with dyslipidaemia.

What role does arterial remodelling play?
Pathologists have described in detail the arterial remodelling occurring in the human coronary arteries [Glagov, 1987].

Definition of arterial remodelling

Arterial remodelling is a feature of the atherosclerotic process by which the growing plaques are found to be eccentric, with a crescent-like shape. The lumen size is, therefore, unaffected, at least in the early stages of the atherosclerotic process.

This finding reveals an important limitation of the invasive coronary angiography, which only evaluates the lumen and fails to demonstrate even extensive plaques, which develop in an outward direction. According to more recent views, the coronary stenoses are the result of superimposed thrombosis, which complicates unstable plaques. It is thrombosis, rather than progressive plaque growth, that leads to flow-reducing stenoses and subsequent myocardial ischaemia and necrosis presenting as acute coronary syndromes (eg, unstable angina, myocardial infarction). Less information is available on arterial remodelling in arterial districts other than the coronary arteries. It is possible to evaluate carotid artery remodelling in humans, by noninvasive B-mode imaging.