MoD S7 - Atheroma

Question 1

Define Atheroma

Answer 1

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

Question 2

Define Atherosclerosis

Answer 2

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

Question 3

Define Arteriosclerosis

Answer 3

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

Question 4

What are the 3 macroscopic features of atheroma?

How do these features reflect atheromatous progression?

Answer 4

Fatty streak
Simple plaque
Complicated plaque

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

Question 5

What is the fatty streak?

Answer 5

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

Question 6

What are the key features of a simple atheromatous plaque?

Answer 6

A raised yellow/white area of the vessel

Irregular outline

Widely distribute

Progressively enlarge and coalesce

Question 7

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

Answer 7

Thrombosis

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

Calcification

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

Question 8

What sites in the vasculature are particularly affected by atheroma?

What about other sites in the vasculature?

Why are these sites in particular vulnerable?

Answer 8

Aorta
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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

Fibrosis (dense fibrotic caps on plaques)

Necrosis

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)

Question 11

What are some of the primary effects of atheroma?

Answer 11

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

Question 12

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

Answer 12

Sudden death
Myocardial infarction
Angina pectoris
Arrhythmias
Cardiac failure

Question 13

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

Answer 13

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

Question 14

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

Answer 14

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

Question 15

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

Answer 15

Intermittent claudication (pain in calves on walking)

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

Ischaemic rest pain

Gangrene

Question 16

What are some of the risk factors for atheroma?

Answer 16

Age
Gender
Hyperlipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus
Alcohol
Infection
Lack of exercise
Obesity
Oral contraceptives
Stress

Question 17

What are the gender differences in risk of atheroma developing?

Answer 17

Affects men more than women

Women relatively pretected before menopause, assumed hormonal basis

Question 18

Why is hyperlipidaemia associated with atheroma?

Answer 18

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

Question 19

How is hypertension related to atheroma?

Answer 19

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

Endothelial damage may be caused by high BP

Question 20

How is diabetes mellitus related to atheroma?

Answer 20

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

Question 21

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

Answer 21

> 5 units per day increases risk of IHD and atheroma

Smaller amounts may be protective

Question 22

Give 3 examples of infection that may increase risk of atheroma

Answer 22

Chlamydia
Helicobacter pylori
Cytomegalovirus

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

Question 23

How is cigarette smoking related to atheroma?

Answer 23

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)

Question 24

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

Answer 24

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

Variations in apolipoprotein receptors

Question 25

How is apolipoprotein E related to atheroma development?

Answer 25

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

Question 26

What is familial hyperlipidaemia? What are some of the associated physical signs?

Answer 26

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)

Question 27

What are the 4 theories of atheroma pathogenesis? How are they all related?

Answer 27

Thrombogenic theory Insudation theory Monoclonal hypothesis Reaction to injury hypothesis Can be collected to form the 'Unified theory'

Question 28

Describe the Thrombogenic theory and Insudation theory of atheroma pathogenesis

Answer 28

Thrombogenic: - 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 Insudation: - 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

Question 29

Describe the Reaction to injury hypothesis of atheroma pathogenesis

Answer 29

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

Question 30

Describe the monoclonal hypothesis of atheroma pathogenesis

Answer 30

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

Question 31

What are the major processes involved in atheroma?

Answer 31

Thrombosis Lipid accumulation Production of intercellular matrix Interactions between cell types

Question 32

What are the different cell types involved in atheroma?

Answer 32

``` Endothelial cells Platelets Smooth muscle cells Macrophages Lymphocytes Neutrophils ```

Question 33

How are endothelial cells involved in atheroma?

Answer 33

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

Question 34

How are platelets involved in atheroma?

Answer 34

Key role in haemostasis Stimulation of proliferation and migration of smooth muscle cells via platelet derived growth factor

Question 35

How are smooth muscle cells involved in atheroma?

Answer 35

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)

Question 36

How are macrophages involved in atheroma?

Answer 36

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

Question 37

How are lymphocytes involved in atheroma?

Answer 37

Produce TNF that may affect lipoprotein metabolism Stimulate proliferation and migration of smooth muscle cells

Question 38

How are neutrophils involved in atheroma?

Answer 38

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)

Question 39

Describe the unified hypothesis of atheroma pathogenesis

Answer 39

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

Question 40

How can atheroma development be prevented?

Answer 40

``` 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

Question 41

How can atheroma be controlled once it has appeared?

Answer 41

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

Question 42

What dietary factors may influence the development of atherosclerosis?

Answer 42

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

Question 43

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

Answer 43

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

Question 44

What factors increase susceptibility to coronary heart disease?

Answer 44

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

Question 45

What are the risk factors for coronary heart disease?

Answer 45

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