ATHEROSCLEROSIS

Atherosclerosis may manifest as coronary heart disease (e.g. angina, myocardial infarction, sudden death), cerebrovascular disease (e.g. stroke and transient ischaemic attack) or peripheral vascular disease (e.g. claudication and critical limb ischaemia). These entities often coexist and the pathogenesis of the disease is similar. Occult coronary artery disease is common in those who present with other forms of atherosclerotic vascular disease, such as intermittent claudication or stroke, and is an important cause of subsequent morbidity and mortality in these patients. PATHOPHYSIOLOGY Atherosclerosis is a progressive inflammatory disorder of the arterial wall that is characterised by focal lipid-rich deposits of atheroma that remain clinically silent until they become large enough to impair arterial perfusion or until ulceration or disruption of the lesion results in thrombotic occlusion or embolisation of the affected vessel. These mechanisms are common to the entire vascular tree, and the clinical manifestations of atherosclerosis depend upon the site of the lesion and the vulnerability of the organ supplied. Atherosclerosis is a disorder that begins early in life; abnormalities of arterial endothelial function have been detected among high-risk children and adolescents (e.g. cigarette smokers and those with familial hyperlipidaemia or hypertension), and early atherosclerotic lesions have been found in the arteries of victims of accidental death in the second and third decades of life. Nevertheless, clinical manifestations often do not appear until the sixth, seventh or eighth decade. Early atherosclerosis Fatty streaks tend to occur at sites of altered arterial shear stress, such as bifurcations, and are associated with abnormal endothelial function. They develop when inflammatory cells, predominantly monocytes, bind to receptors expressed by endothelial cells, migrate into the intima, take up oxidised low-density lipoprotein (LDL) from the plasma and become lipid-laden foam cells or macrophages. Extracellular lipid pools appear in the intimal space when these foam cells die and release their contents. In response to cytokines and growth factors produced by the activated macrophages, smooth muscle cells migrate from the media of the arterial wall into the intima, and change from a contractile to a repair phenotype in an attempt to stabilise the atherosclerotic lesion. If they are successful, the lipid core will be covered by smooth muscle cells and matrix, producing a stable atherosclerotic plaque that will remain asymptomatic until it becomes large enough to obstruct arterial flow. Advanced atherosclerosis In an established atherosclerotic plaque, macrophages mediate inflammation and smooth muscle cells promote repair; if inflammation predominates, the plaque becomes active or unstable and may be complicated by ulceration and superadded thrombosis. Cytokines such as interleukin-1, tumour necrosis factor-alpha, interferon-gamma, platelet-derived growth factors and matrix metalloproteinases are released by activated macrophages and may cause the intimal smooth muscle cells overlying the plaque to become senescent, resulting in thinning of the protective fibrous cap; they may also digest collagen cross-struts within the plaque. These changes make the lesion vulnerable to the effects of mechanical stress and may lead to erosion, fissuring or rupture of the plaque surface. Any breach in the integrity of the plaque will expose its contents to circulating blood and may trigger platelet aggregation and thrombosis that extends into the atheromatous plaque and the arterial lumen. This type of plaque event may cause partial or complete obstruction at the site of the lesion and/or distal embolisation resulting in infarction or ischaemia of the affected organ. It is the common mechanism that underlies many of the acute manifestations of atherosclerotic vascular disease (e.g. acute lower limb ischaemia, myocardial infarction and stroke). The number and complexity of arterial plaques increase with age and with systemic risk factors (see below) but the rate of progression of individual plaques is variable. There is a complex and dynamic interaction between mechanical wall stress and atherosclerotic lesions. 'Vulnerable plaques' are characterised by a lipid-rich core, a thin fibrocellular cap, an increase in inflammatory cells, and the release of specific enzymes that degrade matrix proteins. In contrast, stable plaques are typified by a small lipid pool, a thick fibrous cap, calcification and plentiful collagenous cross-struts. Lipid-lowering therapy may help to stabilise vulnerable plaques. Fissuring or rupture tends to occur at sites of maximal mechanical stress, particularly the margins of an eccentric plaque, and may be triggered by a surge in blood pressure (e.g. during exercise or emotional upset). Surprisingly, plaque events are often subclinical and may heal spontaneously; however, this may allow thrombus to be incorporated into the lesion, producing plaque growth and further obstruction to flow in the arterial lumen. Atherosclerosis may also induce complex changes in the media that lead to arterial remodelling; thus, some arterial segments may slowly constrict (negative remodelling) whilst others may gradually enlarge (positive remodelling). These changes are poorly understood but are important because they may amplify or minimise the degree to which atheroma encroaches into the arterial lumen. page 578 page 579 Figure 18.59 The pathogenesis of atherosclerosis. RISK FACTORS The role and relative importance of many risk factors for the development of coronary, peripheral and cerebrovascular disease have been defined in experimental animal studies, epidemiological studies and clinical interventional trials. Some key factors have emerged but do not explain all the risk; thus, unknown or as yet unconfirmed factors may account for up to 40% of the variation in risk of atheromatous vascular disease from one person to the next. The impact of genetic risk is illustrated by twin studies; for example, a monozygotic twin of an affected individual has an eightfold increased risk, and a dizygotic twin a fourfold increased risk of dying from coronary heart disease compared to the general population. page 579 page 580 The effect of risk factors is multiplicative rather than additive. People with a combination of risk factors (e.g. smoking, hypertension and diabetes) are at greatest risk and assessment should therefore be based on a holistic approach that takes account of all identifiable risk factors. It is also important to distinguish between relative risk (the proportional increase in risk) and absolute risk (the actual chance of an event). Thus, a man of 35 with a plasma cholesterol of 7 mmol/l (∼170 mg/dl) who smokes 40 cigarettes a day is relatively much more likely to die from coronary disease within the next decade than a non-smoking woman of the same age with a normal cholesterol, but the absolute likelihood of his dying during this time is still small (high relative risk, low absolute risk). Age and sex. Age is the most powerful independent risk factor for atherosclerosis. Pre-menopausal women have much lower rates of disease than age- and risk-matched males; however, the gender difference disappears rapidly after the menopause. Randomised controlled trials have demonstrated that hormone replacement therapy has no role in the primary or secondary prevention of coronary heart disease. Indeed, isolated oestrogen therapy appears potentially to cause an increased cardiovascular event rate. Family history. Atherosclerotic vascular disease often runs in families. This may be due to a combination of shared genetic, environmental and lifestyle (e.g. smoking, exercise and diet) factors. The most common inherited risk characteristics (hypertension, hyperlipidaemia, diabetes) are polygenic. A 'positive' family history is present when clinical problems in first-degree relatives occur at relatively young age, such as < 50 years for men and < 55 years for women. Smoking. Smoking is probably the most important avoidable cause of atherosclerotic vascular disease; there is a strong, consistent and dose-linked relationship between cigarette smoking and ischaemic heart disease. Hypertension (see below). The incidence of atherosclerosis increases as blood pressure rises and this excess risk is related to both systolic and diastolic blood pressure as well as pulse pressure. Antihypertensive therapy has been shown to reduce coronary mortality, stroke and heart failure. Hypercholesterolaemia. Robust epidemiological data demonstrate that the risk of coronary heart disease and other forms of atherosclerotic vascular disease rises with plasma cholesterol concentration, and in particular the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol. A much weaker correlation also exists with plasma triglyceride concentration. Extensive large-scale randomised trials have shown that lowering total LDL and cholesterol concentrations reduces the risk of cardiovascular events including death, myocardial infarction and stroke, and also reduces the need for revascularisation. Diabetes mellitus. This is a potent risk factor for all forms of atherosclerosis and is often associated with diffuse disease that is difficult to treat. Insulin resistance (normal glucose homeostasis with high levels of insulin) is associated with obesity and physical inactivity, and is also a potent risk factor for coronary heart disease. Glucose intolerance accounts for a major part of the high incidence of ischaemic heart disease in certain ethnic groups, e.g. South Asians. Haemostatic factors. Platelet activation and high levels of fibrinogen are associated with an increased risk of coronary thrombosis. Anti-phospholipid antibodies are associated with recurrent arterial thomboses. Physical activity. Physical inactivity roughly doubles the risk of coronary heart disease and is a major risk factor for stroke. Regular exercise (brisk walking, cycling or swimming for 20 minutes two or three times a week) appears to have a protective effect which may be related to increased HDL cholesterol, lower blood pressure, reduced blood clotting, and collateral vessel development. Obesity (p. 111). Obesity, particularly if central or truncal, is an independent risk factor, although it is often associated with other adverse factors such as hypertension, diabetes and physical inactivity. Alcohol. A moderate intake of alcohol (2-4 units a day) appears to offer some protection from coronary disease; however, heavy drinking is associated with hypertension and excess cardiac events. Other dietary factors. Diets deficient in fresh fruit, vegetables and polyunsaturated fatty acids are associated with an increased risk of vascular disease. Low levels of vitamin C, vitamin E and other antioxidants may enhance the production of oxidised LDL. Hyperhomocysteinaemia is associated with accelerated atherosclerosis including stroke and peripheral vascular disease. Low dietary folate, vitamin B12 and vitamin B6 can elevate homocysteine concentrations. Personality. Certain personality traits are associated with an increased risk of coronary disease. Nevertheless, there is little or no evidence to support the popular belief that stress is a major cause of coronary artery disease. 18.49 POPULATION ADVICE TO PREVENT CORONARY DISEASE Do not smoke Take regular exercise (minimum of 20 mins, three times a week) Maintain 'ideal' body weight Eat a mixed diet rich in fresh fruit and vegetables Aim to get no more than 10% of energy intake from saturated fat PRIMARY PREVENTION Two complementary strategies can be used to prevent atherosclerosis in apparently healthy but at-risk individuals. The population strategy aims to modify the risk factors of the whole population through diet and lifestyle advice on the basis that even a small reduction in smoking or average cholesterol, or modification of exercise and diet will produce worthwhile benefits. Some risk factors for atheroma, such as obesity and smoking, are also associated with a high risk of other diseases and should be actively discouraged through public health measures. In contrast, the targeted strategy aims to identify and treat high-risk individuals, who usually have a combination of risk factors and can be identified by using composite scoring systems. It is important to consider the absolute risk of atheromatous cardiovascular disease that any one individual is facing before contemplating specific antihypertensive or lipid-lowering therapy because this will help to determine whether the possible benefits of intervention are likely to outweigh the expense, inconvenience and possible side-effects of treatment. For example, a 65-year-old man with an average blood pressure of 150/90 mmHg, who smokes and has diabetes, a total:HDL cholesterol of 8 and left ventricular hypertrophy on ECG, will have a 10-year risk of CHD of 68% and a 10-year risk of any cardiovascular event of 90%. Lowering his cholesterol will reduce these risks by 30% and lowering his blood pressure will produce a further 20% reduction; both treatments would obviously be worth while. Conversely, a 55-year-old woman who has an identical blood pressure, is a non-smoker, is not diabetic and has a normal ECG and a total:HDL cholesterol of 6 has a much better outlook, with a predicted CHD risk of 14% and cardiovascular risk of 19% over the next 10 years. Although lowering her cholesterol and blood pressure would also reduce risk by 30% and 20% respectively, the value of both forms of treatment would clearly be questionable. There is strong observational evidence that moderate to high levels of physical activity reduce the risk of coronary heart disease and stroke (relative risk reduction 30-50%). Observational studies have found that the risk of death and cardiovascular events falls when people stop smoking. SECONDARY PREVENTION page 580 page 581 18.50 USE OF STATINS IN PREVENTION OF ATHEROSCLEROTIC DISEASE Primary prevention 'In patients without evidence of coronary disease but with high cholesterol levels, cholesterol-lowering with statins does not significantly lower mortality but does prevent coronary events (angina and myocardial infarction).' Secondary prevention 'In patients with established coronary disease (MI or angina), statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation and stroke by about one-fifth per mmol/l reduction in LDL cholesterol concentration. Benefit depends on the overall risk of the study population but the NNTBs for 5 years to prevent one death range from 10 to 90.' LaRosa JC, et. al. JAMA 1999; 282:2340-2346. Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344:1383-1389. Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22. Cholesterol Treatment Trialists' Collaborators. Lancet 2005; 366:1267-1277.

For further information: http://www.sign.ac.uk" target="_blank">www.sign.ac.uk

18.51 ACE INHIBITORS AND SECONDARY PREVENTION OF ATHEROSCLEROTIC DISEASE

'ACE inhibitor therapy reduces the risk of death, myocardial infarction and stroke in patients with atherosclerotic vascular disease without apparent left ventricular systolic dysfunction or heart failure. NNTB to avoid one event over 4 years ranges from 6 to 50 depending upon the level of cardiovascular risk.'

HOPE trial. N Engl J Med 2000; 342:145-153. EUROPA trial. Lancet 2003; 362:782-788.

18.52 ASPIRIN AND SECONDARY PREVENTION IN ATHEROSCLEROTIC VASCULAR DISEASE

'In patients with established ischaemic heart disease, peripheral vascular disease or thrombotic stroke, aspirin is effective in reducing morbidity and mortality (non-fatal myocardial infarction, stroke and cardiovascular death). In patients at high risk of future vascular events, the overall risk reduction is 22%.'

Antithrombotic Trialist Collaboration. BMJ 2002; 324:71-86. Hennekens C, et al. Circulation 1989; 80:749-756.

For further information: http://www.clinicalevidence.org" target="_blank">www.clinicalevidence.org

Patients who already have evidence of atheromatous vascular disease (e.g. peripheral vascular disease or myocardial infarction) are at high risk of another vascular event and can be offered a variety of treatments and measures that have been shown to improve their outlook (secondary prevention). The energetic correction of risk factors, particularly smoking, hypertension and hypercholesterolaemia, is particularly important in this patient group because the absolute risk of further vascular events is very high. In the light of recent randomised controlled trials, especially the Heart Protection Study, all patients with coronary heart disease should be given statin therapy irrespective of their serum cholesterol concentration. Blood pressure should be treated to a target of ≤ 130/80. Aspirin and ACE inhibitors are of benefit in all patients with evidence of vascular disease. Beta-blockers will benefit patients with a history of myocardial infarction (see below) or heart failure.

Many clinical events offer an unrivalled opportunity to introduce effective secondary preventive measures. For example, patients who have just survived a myocardial infarction or undergone bypass surgery are usually keen to help themselves and may be particularly receptive to appropriate lifestyle advice, such as weight reduction, stopping smoking etc.