MoD S7 - Atheroma Flashcards
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?
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
What sites in the vasculature are particularly affected by atheroma?
What about other sites in the vasculature?
Why are these sites in particular vulnerable?
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
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)
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)
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 Arrhythmias 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)
Malabsorption
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
Gangrene
What are some of the risk factors for atheroma?
Age Gender Hyperlipidaemia Cigarette smoking Hypertension Diabetes mellitus Alcohol Infection Lack of exercise Obesity Oral contraceptives Stress
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
Chlamydia
Helicobacter pylori
Cytomegalovirus
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
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
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?
Thrombosis
Lipid accumulation
Production of intercellular matrix
Interactions between cell types
What are the different cell types involved in atheroma?
Endothelial cells Platelets Smooth muscle cells Macrophages Lymphocytes Neutrophils
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?
Smoking Gender (More prevalent in males) Hypertension (increased endothelial damage) Diabetes mellitus (increased IHD risk) Alcohol (>5 units/day) Infection (E.g. helicobacter pylori)
