Risk factors are either non-modifiable or modifiable:

Risk factors for clinical atherosclerosis
Non-modifiable	Modifiable*
Age Male gender Family history of CHD Presence of CHD Menopause	Biomedical	Dyslipidaemia Hypertension Diabetes
	Behavioural	Smoking
	Lifestyle	Physical inactivity Diet
* These are firmly established risk factors supported by the results of many epidemiological, clinical and experimental studes.

What is the role of plasma cholesterol?
In epidemiological studies, high concentrations of plasma cholesterol (hypercholesterolaemia) are closely associated with the development of clinical atherosclerosis both within and between populations. In the inherited disease, known as familial hypercholesterolaemia, the pronounced elevation of LDL concentrations leads to extensive and premature atherosclerosis, involving coronary arteries and causing CHD.

What is the role of oxidised LDL?
Experimental evidence has been provided of enhanced atherogenicity of LDLs when they undergo oxidative modifications [Diaz, 1997; Tribble, 1999]. Vitamin E that is carried in blood within LDL particles is thought to be the first line of protection against oxidation. Oxidised LDLs start an inflammatory reaction in the arterial wall, involving the production of several molecular signals, which are responsible for the cellular responses involved in atherogenesis. In particular, during fatty streak formation (see Figure 3) adhesion molecules and receptors for circulating monocytes and platelets are expressed on the surface of endothelial cells. Circulating lipoproteins, once they have entered the arterial wall, undergo phagocytosis by macrophages, derived from circulating monocytes. Macrophages thus remove LDLs, particularly those that have been oxidised within the arterial wall by interaction with platelets and other cells of the intima. This process is enhanced in the presence of high circulating levels of LDL or remnant particles (see Plasma lipids and lipoprotein), deriving from the catabolism of triglyceride-rich lipoproteins. Macrophages become progressively replete of lipids and are transformed into foam cells. The foam cells eventually undergo necrosis, thus releasing their lipid content into the extracellular matrix.

What is the role of triglycerides?
Hypertriglyceridaemia is associated with a high risk of cardiovascular manifestations, particularly CHD, both in cross-sectional and prospective epidemiological studies [Austin, 1997; Gaziano, 1997]. Many mechanisms have been proposed to explain the atherogenicity of high triglyceride plasma levels and, among these, an important role has been given to the action of high plasma concentrations of remnants, especially during the postprandial phase. In subjects at high risk of CHD, circulating plasminogen-activator inhibitor (PAI) levels are elevated and are associated with impaired fibrinolysis and increased risk of atherothrombosis [Juhan-Vague, 2000]. Other potential mechanisms of atherogenesis secondary to hypertriglyceridaemia include low levels of HDL, the enhanced formation of small dense LDL (see Figure 5), which are characterised by pronounced atherogenicity and oxidability, and the interference in haemostatic processes and fibrinolysis.

What is the role of HDL?
There is strong epidemiological evidence relating low plasma concentrations of HDL-C to CHD. The mechanism underlying cardiovascular protection of high levels of HDL-C has not, however, been fully elucidated [Stein, 1999]. One possibility is that high concentrations of HDL promote RCT (see Centripetal lipoprotein transport: reverse cholesterol transport) from the arterial wall towards the liver, for final excretion in the form of bile salts. Another hypothesis is that HDL may antagonise oxidative processes, possibly through the action of paraoxonase [Mackness, 1998], an antioxidant enzyme that is carried within HDL particles and occurs in low concentrations in the plasma when HDL-C is reduced.

What is the role of angiotensin II?
Plasma concentrations of angiotensin II, the end product of the renin-angiotensin system, are often elevated in patients with hypertension. Angiotensin II has pronounced vasoconstrictive effects and has been suggested to contribute to atherogenesis, by stimulating smooth muscle cell proliferation [Ross, 1999], by enhancement of protein synthesis and eventually hypertrophy of smooth muscle cells. These cells produce great amounts of proteoglycan, collagen and elastic fibres, thereby contributing to the early stages of the atherosclerotic process and to the fibrous component of the plaque. Angiotensin II is also associated with enhanced activity of smooth muscle cell lipoxygenase, causing LDL oxidation.

Diabetes
There is wide epidemiological evidence of the independent association of diabetes mellitus with premature and severe atherosclerosis. Both type 1 and type 2 diabetes are associated with a markedly increased risk of CHD, cerebrovascular disease and peripheral vascular disease. Diabetes is a particularly strong cardiovascular risk factor in women and reduces the relative protection of female gender against atherosclerosis.

What are the causes of premature atherosclerosis?
To some extent the premature atherosclerosis is related to the diabetic dyslipidaemia (consisting of hypertriglyceridaemia and low HDL-C levels) and hypertension, which are highly prevalent among patients with diabetes. However, there is evidence that a part of this excess risk must be caused by the direct effect of hyperglycaemia.

What are the effects of hyperglycaemia?
The mechanisms of increased atherogenesis owing to hyperglycaemia are not completely understood, but there are many experimental studies showing the occurrence of endothelial damage, associated with persisting hyperglycaemia and enhanced production of advanced glycosylation end products and free radicals. In addition, it has been postulated that the presence of insulin resistance and/or hyperinsulinaemia, which are common features of type 2 diabetes, might also contribute to the accelerated atherogenesis observed in individuals with diabetes.

Smoking
Cigarette smoking is universally and strongly associated with clinical atherosclerosis. Among the many toxic substances that are present in tobacco smoke, nicotine is considered the most dangerous for the arterial circulation. In general, cigarette smoking is thought to promote oxidative processes, in addition to producing haemodynamic stress (repeated transitory increases in blood pressure and heart rate) [Avogaro, 1993; Winniford, 1990].

Nutrition
A large body of evidence supports a major role for nutritional factors in the development of atherosclerosis. Several large-scale epidemiological studies have shown an association between a low- saturated fat, low-cholesterol and fibre-rich diet and low prevalence of clinical atherosclerosis. Furthermore, a direct relationship has been demonstrated between dietary trans-fatty acids and cardiovascular disease.

What role do nutritional factors play?
These associations are certainly mediated by the effects of diet on atherosclerotic risk factors, namely plasma lipids and lipoproteins, but the paradigm that nutritional factors influence atherosclerosis exclusively via effects on plasma lipids has been challenged. In particular, in the Lyon Diet Heart Study, survivors of a previous myocardial infarction who were randomly allocated to the 'Mediterranean diet' showed a clear reduction in the rate of cardiovascular events without major effects on the classical risk factors, including plasma lipids [de Lorgeril, 1999].

Obesity
Large prospective studies have found that obesity is associated with increased mortality owing to clinical atherosclerosis. Abdominal obesity is a strong predictor of myocardial infarction and stroke [Wood, 1998]. The association between obesity and, in particular, visceral adiposity and CHD, is largely mediated by their adverse influence on a number of other classical cardiovascular risk factors such as diabetes and dyslipidaemia (especially high triglycerides and low HDL-C) and hypertension.

Exercise
The association between a sedentary lifestyle and an increased risk for cardiovascular diseases has been reported in many epidemiological studies [Wood, 1998]. Even a modest change in lifestyle with the adoption of moderate physical activity may be beneficial. Moreover, there have been many randomised trials on the effects of physical exercise after myocardial infarction showing a clear reduction in cardiovascular mortality.

Homocysteine
High plasma levels of the sulphur-containing amino acid homocysteine have been associated with increased cardiovascular risk [Robinson, 1998]. Some inherited diseases of metabolism have been associated with pronounced hyperhomocysteinaemia and vascular disease [Bellamy, 1997]. Moderate hyperhomocysteinaemia, owing to vitamin deficit, has also been demonstrated to be a potential risk factor for cardiovascular manifestations [Robinson, 1998]. Despite the large body of evidence supporting high homocysteine plasma levels as predictors of cardiovascular diseases, it may be more appropriate to consider hyperhomocysteinaemia as a risk indicator rather than a risk factor, in view of the lack of large-scale intervention trials.