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Define Atheroma

Atheroma is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries


Define Atherosclerosis

The thickening and hardening of the arterial walls as a consequence of atheroma


Define Arteriosclerosis

The thickening of the walls of arteries and arterioles as a result of hypertension or diabetes mellitus


What are the 3 macroscopic features of atheroma?

How do these features reflect atheromatous progression?

Fatty streak
Simple plaque
Complicated plaque

Constitute a spectrum of progression from the fatty streak to complicated plaque as atheroma worsens


What is the fatty streak?

Lipid deposits in the intima

Appear as a slightly raised yellow streak along the intima

Relationship to atheroma somewhat debated as it is found in regions of the body not prone to atheroma and in populations where atheroma isn't as prevalent


What are the key features of a simple atheromatous plaque?

A raised yellow/white area of the vessel

Irregular outline

Widely distribute

Progressively enlarge and coalesce


What are some complications that can occur as a result of atheromatous plaques being present in an artery?


Haemorrhage into the plague:
- Unstable plaque disrupted by blood flow at high pressure allowing haemorrhage into the vessel wall


Aneurysm formation:
- As atheroma becomes more extensive in the tunica media the elastic tissue is affected and number of elastic fibres is reduced, aneurysm forms via stretching of the vessel wall


What sites in the vasculature are particularly affected by atheroma?

What about other sites in the vasculature?

Why are these sites in particular vulnerable?

Coronary arteries
Carotid arteries
Cerebral arteries
Leg arteries

Other sites in the body are less likely to develop plaques

Not known why these sites are particularly effected


What are the early microscopic changes seen in someone developing atheroma?

Proliferation of smooth muscle cells

Accumulation of foam cells (macrophages and smooth muscle cells with cytoplasmic lipid accumulation)

Extracellular lipid in the wall of the artery

Abnormalities in the composition of the extracellular matrix


What are the later microscopic changes seen in someone with atheroma?

Fibrosis (dense fibrotic caps on plaques)


Cholesterol clefts:
- Cholesterol crystallises and forms needle shaped crystals, these are dissolved in histological preparation and we see the 'cleft' left behind

Inflammatory cells:
- Widely varies, may influence stability, likelihood of thrombosis and aneurysm formation

Disruption of internal elastic lamina

Damage extends to media

Ingrowth of blood vessels into the plaque (new 'leaky' capillaries, may contribute to haemorrhage into plaque)

Plaque fissuring (due to sheering forces of blood against an unstable plaque)


What are some of the primary effects of atheroma?

Ischaemic heart disease
Cerebral ischaemia
Mesenteric ischaemia
Peripheral vascular disease
Abdominal aortic aneurysm (AAA)


List some of the conditions that may be a result of ischaemic heart disease due to atheroma

Sudden death
Myocardial infarction
Angina pectoris
Cardiac failure


What are some of the conditions that may be a result of cerebral ischaemia due to atheroma?

Transient ischaemia attach
Cerebral infarction
Multi-infarct dementia (multiple small infarcts that affect cognitive function leading to dementia)


What are some of the conditions that result from mesenteric ischaemia due to atheroma?

Ischaemic colitis (chronic, leads to abdominal pain/bleeding)
Intestinal infarction


What are some of the conditions that result from peripheral vascular disease due to atheroma?

Intermittent claudication (pain in calves on walking)

Leriche syndrome (pain in buttocks, impotence due to atheroma of the iliac artery)

Ischaemic rest pain



What are some of the risk factors for atheroma?

Cigarette smoking
Diabetes mellitus
Lack of exercise
Oral contraceptives


What are the gender differences in risk of atheroma developing?

Affects men more than women

Women relatively pretected before menopause, assumed hormonal basis


Why is hyperlipidaemia associated with atheroma?

High plasma cholesterol associated with atheroma
LDL most significant
HDL is protective


How is hypertension related to atheroma?

There is a strong link between high BP and Ischaemic heart disease

Endothelial damage may be caused by high BP


How is diabetes mellitus related to atheroma?

Diabetes mellitus doubles ischaemic heart disease risk

Also associated with cerebrovascular and peripheral vascular disease

May also be related to hyperlipidaemia and hypertension, raising risk of atheroma further


At what level of alcohol consumption does risk of atheroma increase?

>5 units per day increases risk of IHD and atheroma

Smaller amounts may be protective


Give 3 examples of infection that may increase risk of atheroma

Helicobacter pylori

This association is mostly theoretical at this point, no conclusive evidence


How is cigarette smoking related to atheroma?

Powerful risk factor for IHD

Risk falls after giving up

Mode of action uncertain:
- May work via the coagulation system
- May cause reduced prostacyclin
- Hence causing increased platelet aggregation
- This may lead to atherogenesis (We're not sure)


What are some genetic factors that may predispose to atheroma development?

Variations in apolipoprotein metabolism
(E.g. Familial hyperlipidaemia)

Variations in apolipoprotein receptors


How is apolipoprotein E related to atheroma development?

Genetic variations in Apo E are associated with changes in LDL levels

Polymorphisms of the genes involved lead to at least 6 phenotypes

These phenotypes can be used as risk markers for atheroma


What is familial hyperlipidaemia?

What are some of the associated physical signs?

Genetically determined abnormalities of lipoproteins

These lead to early development of atheroma

Associated physical signs include:
- Corneal Arcus (ring around the cornea)

- Tendon xanthomas (cholesterol rich lipid deposition in tendons)

- Xanthelasma (raised deposits of fat around the eyes/eyelids)


What are the 4 theories of atheroma pathogenesis?

How are they all related?

Thrombogenic theory

Insudation theory

Monoclonal hypothesis

Reaction to injury hypothesis

Can be collected to form the 'Unified theory'


Describe the Thrombogenic theory and Insudation theory of atheroma pathogenesis

- Plaques formed by repeated thrombi sticking to the arterial wall
- Then somehow becoming associated with lipid
- A cap then forms over the thrombus
- This is repeated over and over as the plaques grow

- Some method of endothelial injury
- This leads to inflammation
- This increases the permeability of the vessel wall to lipids allowing lipids into the vessel wall from the plasma


Describe the Reaction to injury hypothesis of atheroma pathogenesis

Plaques form in response to endothelial injury

Hyperlipidaemia leads to the endothelial damage

Injury increases permeability and allows platelet adhesion

Monocytes penetrate into endothelium and become foam cells

Smooth muscle cells proliferate and migrate

Later suggested that:
- Endothelial injury was so subtle as to be undetectable visually
- Oxidised LDL may be what is damaging the endothelium


Describe the monoclonal hypothesis of atheroma pathogenesis

Smooth muscle cell proliferation is crucial

Each plaque is monoclonal

Each plaque might therefore represent a benign tumour due to abnormal growth control

Also a viral aetiology suggested


What are the major processes involved in atheroma?

Lipid accumulation
Production of intercellular matrix
Interactions between cell types


What are the different cell types involved in atheroma?

Endothelial cells
Smooth muscle cells


How are endothelial cells involved in atheroma?

Key role in haemostasis (pro and anti coagulant effects)

Their permeability to lipoproteins is altered

They secrete collagen (major structural protein in the plaques, may be abnormal in atheroma)

Stimulate the proliferation and migration of smooth muscle cells


How are platelets involved in atheroma?

Key role in haemostasis

Stimulation of proliferation and migration of smooth muscle cells via platelet derived growth factor


How are smooth muscle cells involved in atheroma?

Proliferate and migrate

Take up LDL and other lipids and become foam cells

Synthesise collagen and proteoglycans (for the intercellular matrix that may be abnormal in atheroma)


How are macrophages involved in atheroma?

Oxidise LDL

Take up lipids and become foam cells

Secrete proteases which modify matrix (can have an effect on plaque stability/rupture/fissure)

Stimulate the proliferation and migration of smooth muscle cells


How are lymphocytes involved in atheroma?

Produce TNF that may affect lipoprotein metabolism

Stimulate proliferation and migration of smooth muscle cells


How are neutrophils involved in atheroma?

Secrete proteases leading to continued local damage and inflammation, which then in turn may lead to atheroma

Proteases can also modify the proteins of the intercellular matrix affecting the stability of the plaque (more likely to rupture/fissure)


Describe the unified hypothesis of atheroma pathogenesis

Subtle endothelial injury due to:
- Raised LDL
- Toxins (E.g. Cigarette smoke)
- Hypertension
- Haemodynamic stress

This injury leads to:
- Platelet adhesion, platelet derived growth factor release and subsequent smooth muscle cell proliferation and migration
- Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
- Migration of monocytes into intima

Stimulated smooth muscle cells then produce matrix material

Foam cells secrete cytokines causing:
- Further smooth muscle cell stimulation
- Recruitment of other inflammatory cells


How can atheroma development be prevented?

No smoking
Reduce fat intake
Treat hypertension
Limit alcohol
Regular exercise/weight control

However some people will still develop atheroma even if they adhere to all these points


How can atheroma be controlled once it has appeared?

Stop smoking
Modify diet
Treating hypertension (if present)
Treating diabetes (if present)
Lipid lowering drugs (statins)


What dietary factors may influence the development of atherosclerosis?

Unsaturated fats that will raise levels of LDL in the blood are going to increase the chance of developing atherosclerosis if eaten in excess


What dietary advice might a physician give to a patient at risk of atherosclerosis?

Reduce unsaturated fat intake

Eat a balanced diet, include more fruits and vegetables, lean protein sources

Limit cholesterol intake

Limit total fat and calorie intake

Reduce salt intake


What factors increase susceptibility to coronary heart disease?

Genetic (E.g. Familial hypercholesterolaemia)
Geographical - Less common in the mediterranean (diet)
Ethnicity - CHD more common in Asians


What are the risk factors for coronary heart disease?

Gender (More prevalent in males)
Hypertension (increased endothelial damage)
Diabetes mellitus (increased IHD risk)
Alcohol (>5 units/day)
Infection (E.g. helicobacter pylori)