Pathophysiology^[1][2]

Atherosclerotic plaques form in the arterial wall. Previously, plaque formation was considered as a cholesterol storage disease. It is now regarded as a complex process involving interaction between the arterial wall and blood components, with inflammation playing a major role.

Plaque formation

Plaque formation involves smooth muscle cells, leukocytes, and various mediators of inflammation and immunity, including cytokines and complement components.^[2] The first lesion seen is the fatty streak, which may develop into a plaque. Plaques have a lipid core and a fibrous cap.

Atherosclerotic plaques tend to occur in regions where vessels branch, curve or are irregular, where blood undergoes sudden changes in velocity and in direction of flow.

The traditional view of atherosclerosis was that plaques produce arterial narrowing, ie stenoses. The degree of stenosis was thought to be the main factor in diseases such as coronary artery disease. Recent understanding is that plaques grow outward rather than inward for much of their life history, so that substantial atherosclerosis can exist without producing stenosis. Hence, significant atherosclerosis may be silent clinically and invisible on angiograms. Stenoses are the 'tip of the iceberg' of atherosclerosis.

Nitric oxide may play a key role in the pathogenesis of atherosclerosis.^[3]

Plaque rupture and thrombosis

Acute clinical complications of atherosclerosis, such as acute coronary syndromes and ischaemic stroke, are usually due to rupture of a plaque leading to thrombosis, with partial or complete obstruction of the artery.

Some plaques are more prone to rupture than others. 'High-risk' plaques are those with a thin cap and a large lipid core containing relatively more inflammatory cells and fewer smooth muscle cells. These 'vulnerable plaques' may be widespread and yet may not produce stenosis or ischaemia, so they are a hidden threat to health. This type of plaque tends to produce an acute problem (eg acute coronary syndrome), whereas a more stable and stenotic plaque will produce a more chronic clinical picture (eg stable angina).

These concepts of widespread and vulnerable plaques have implications for management, making it important to treat cardiovascular disease (CVD) not only with revascularisation procedures, but with systemic treatments aimed at stabilising plaques and reducing thromboses.

Epidemiology

Although atherosclerosis usually manifests in later life, its early phases are present in teenagers and young adults.^[4]

The clinical manifestations of atherosclerosis, such as cardiovascular disease (CVD), are common in Western and urban populations, and are an important and common cause of death and disease.

Risk factors

Many risk factors have been identified for atherosclerotic disease; the main ones are listed here. Note that most of the literature on this topic relates to the clinical manifestations of atherosclerosis, mainly rates of cardiovascular disease and coronary heart disease.

Risk factors for CVD^[1][5]

Permanent factors:

• Increasing age.
• Male gender.
• Family history of early coronary heart disease (eg in men <55 years and women <65 years).
• Race, eg many South Asian races at higher risk.

Lifestyle, social and environmental factors:

• Cigarette smoking.
• Lack of regular physical exercise.
• Diet:
  • Lack of fruit and vegetables.
  • High-fat - the type of fat is important, eg trans fats increase CVD risk.
  • Lower intake of omega-3 fatty acids (eg in fish oils).^[6][7]
• High alcohol intake (moderate alcohol intake may be protective).
• Psychosocial factors (eg stress at work or home, depression^[5] and deprivation^[8]).
• Air pollution (possibly).^[9]

Coexisting conditions:

• Hypertension.
• Diabetes mellitus (probably through mechanisms of hyperglycaemia, lipoprotein abnormalities, and inflammation^[10]).
• Hyperlipidaemia:
  • Raised low-density lipoprotein (LDL) cholesterol.
  • High-density lipoprotein (HDL) cholesterol and its apolipoproteins (apos) A-I and A-II are protective.^[11][12]
  • Raised triglycerides (possibly).^[13]
• Obesity, particularly abdominal obesity (including metabolic syndrome).^[14]
• Systemic inflammation, eg in systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, human immunodeficiency virus, systemic sclerosis, vasculitis and periodontitis.^[15]
• Low levels of vitamin D (possibly).^[16]
• Obstructive sleep apnoea (possibly).^[17]

Metabolic factors:

• Raised C-reactive protein.
• Raised fibrinogen and raised lipoprotein (a) (possibly).
• Homocysteine - raised plasma homocysteine levels have been linked to atherosclerosis, but there seems to be no cardiovascular benefit from vitamins lowering homocysteine (folic acid and B vitamins).^[18]

Presentation

• Atherosclerosis in its early stages is silent.
• The clinical presentation is usually with complications (see below).
• Possible signs are:
  • Xanthelasmata (from hyperlipidaemia).
  • Bruits over large arteries (eg carotid bruits).
  • Aortic aneurysm.
  • Poor peripheral pulses.
  • Reduced ankle-brachial index.^[19]

Complications^[1]

• Coronary heart disease:
  • Stable angina.
  • Acute coronary syndromes - unstable angina and myocardial infarction.
• Cerebrovascular disease:
  • Stroke.
  • Transient ischaemic attack.
• Aortic aneurysm
• Peripheral vascular disease:
  • Claudication.
  • Acute limb ischaemia.
• Visceral ischaemia:
  • Renal artery stenosis.
  • Mesenteric angina and mesenteric infarction.
• Atheroembolic disease:
  • This is the release of cholesterol crystals into arteries, usually following vascular surgery, catheterisation or anticoagulation.
  • May affect various organs - kidneys (atheroembolic renal disease), skin, gastrointestinal system, and brain.^[20][21]

Investigation^[4]

Investigation of atherosclerosis itself (rather than its clinical manifestations) is not routine in clinical practice, but has been used as a research tool. Possible techniques are:^[4]

• Ultrasound measurement of carotid intima-media thickness using B-mode ultrasound - this has some limitations.^[22]
• Intravascular ultrasound - can detect atherosclerotic plaques not visible on angiography; may show up recent plaque disruption.^[1]
• High-resolution MRI.
• CT - multislice spiral CT or electron beam CT to quantify coronary artery calcium.^[23]

Management and prevention^[1][2][4]

Established management

There are existing guidelines for:

• Assessment of cardiovascular risk.^[24]
• Primary prevention of cardiovascular disease (CVD).
• Secondary prevention of cardiovascular disease.

As an overview, standard prevention and treatment involve:

• Lifestyle modifications:
  • Smoking cessation.
  • Diet - increased fruit and vegetables, reduced fat intake, increased omega-3 fatty acid intake.
  • Regular physical exercise.
  • Avoiding excess alcohol.
• Treat contributing disease, eg diabetes, hypertension; treat complications.
• Drug treatment:
  • Statins - have effects on both lipids and inflammation. There is some evidence that statins prevent progression and may even reverse coronary atherosclerosis.^[4]
  • Omega-3 fatty acids - currently prescribable as adjunct in secondary prevention for those with myocardial infarction in the previous three months, or for hypertriglyceridaemia.^[25] Also available over-the-counter as supplements.
  • Antiplatelet drugs - aspirin and others, are used for those at greatest risk (eg in secondary prevention of CVD).^[2]

Newer treatments and research

Note that when considering the effectiveness of new treatments, it is important to consider whether they improve patient outcomes, rather than focusing on biomarkers such as lipid levels.^[26]

Drugs:^[11][12]

• Nicotinic acid can effectively raise high-density lipoprotein (HDL) cholesterol levels. Research on prolonged-acting nicotinic is ongoing.
• Fibrates reduce low-density lipoprotein (LDL) cholesterol, reduce triglycerides and increase HDL cholesterol, and may improve CVD outcomes.
• The cholesterol-absorption inhibitor ezetimibe has a small effect in raising HDL cholesterol, which is potentiated by combining it with a statin or fibrate.
• Pharmacological inhibitors of the cholesteryl ester transfer protein (CETP) offer a potentially novel mechanism for raising HDL cholesterol levels.

Diet:

• Plant stanols and sterols reduce LDL cholesterol levels and have other potentially beneficial effects, but their effect on CVD and atherosclerosis is unknown.^[27]
• A fruit and vegetable-rich diet is protective for CVD. The mechanism is uncertain, but it may be related to dietary inorganic nitrate, found particularly in leafy green vegetables.^[28]
• Specific foods that may be protective for CVD are: lycopenes (a carotenoid found in tomatoes),^[29] polyphenols (found in red wine and tea)^[30] and pomegranate juice.^[31]
• Dietary patterns and markers of inflammation are linked, and this may be relevant to the development of atherosclerosis.^[32]
• Moderate alcohol intake may protect against coronary artery disease, by various mechanisms. However, when advising patients about alcohol consumption and heart health there are various factors to consider.^[33][34]