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Flashcards in MOD 6 Deck (55):

Define athersclerosis

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


Define atheroma

The accumulation of intracellular and extracellular lipids in the intima and media of medium and large sized arteries.


Define arteriosclerosis

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


Describe the cellular events that cause chronic endothelial injury:

1. raised LDL
2. 'toxins' e.g. cigarette smoke
3. hypertension
4. Haemodynamic stress


Describe the effects of endothelial injury on platelets, smooth muscle cells, lipid, macriphages and monocytes:

Endothelial injury causes:
1. Platelets: PDGF release
2. Smooth muscle cells: proliferation, migration and uptake of lipid
3. Lipid: insudation, LDL oxidation
4. Macrophages: uptake of lipid, migration of monocytes into intima.


What is the macroscopic morphological appearance of atheroma?

1. Fatty streak
2. Simple plaque
3. Complicated plaque (calcification, thrombosis, haemorrhage, aneurysm formation)


What is the microscopic morphological appearance of the early changes of atheroma?

1. Accumulation of foam cells
2. Proliferation of smooth muscle cells
3. Extracellular lipid deposition


What is the microscopic morphological appearance of the later changes of atheroschlerosis?

1. Fibrosis
2. Necrosis
3. Cholesterol clefts
4. +/- inflammatory cells
5. Disruption of internal elastic lamina
6. Damage extends into tunica media
7. Ingrowth of blood vessels
8. Plaque fissuring


What is an aneurysm?

An excessive localised swelling of the wall of an artery.


List some clinical effects of ischaemic heart disease:

1. Sudden death
2. Myocardial infarction
3. Angina pectoris - chest pain on exertion
4. Arrythmias e.g. AF, these can be fatal
5. Cardiac failure - scarred heart, peripheral oedema and SOB


List some clinical effects of cerebral ischaemia?

1. Transient ischaemic attack (mini stroke)
2. Cerebral infarction (stroke)
3. Multi-infarct dementia


List some clinical effects of mesenteric ischaemia?

1. Ischaemic colitis - present with rectal bleeding and sometimes abdominal pain
2. Malabsorption
3. Intestinal infarction - thrombus or embolus in branch of SMA


List some clinical effects of peripheral vascular disease?

1. Intermittent claudication - pain in legs due to reduced blood supply
2. Leriche syndrome - pain in buttocks - associated with impotence as a result of impaired blood supply
3. Ischaemic rest pain - muscle hurt without exercise, if left untreated -> gangrene
4. Gangrene - loss of blood supply leading to visible necrosis.


List the different hypotheses for the mechanism of atherogenesis:

Unifying hypotheses
Historical hypotheses
Response to injury/insudation hypothese
Encrustation hypothese
Monoclonal hypothese
Lipid oxidation hypothese


What cells are involved in atherogenesis?

Endothelial cells, platelets, smooth muscle cells, macrophages, lymphocytes and neutrophils.


List some risk factors for atherosclerosis:

age, gender, Smoking, hypertension, impaired glucose tolerance, hyperlipidaemia, alcohol, apoliprotein E genotype, geography, infection


What changes in lifestyle can you make to reduce the risk of atheroschlerosis?

1. Stop smoking
2. Decrease fat intake
3. Sensible alcohol intake
4. Regular exercise and control of weight


What therapeutic interventions can reduce the risk of atherosclerosis?

1. Treat hypertension e.g. beta blockers
2. Aspirin
3. Treat diabetes mellitus
4. Lipid lowering drugs where needed e.g. statins


The first sign of an atheroma is thought to be a fatty streak. What does this look like macroscopically?

Yellow and slighly raised due to lipid deposits in the intima. However its relation to atheroma is somewhat debatable - does have slightly different anatomical locations.


What does the simple plaque stage of atheromas look like macroscopically?

1. Raised yellow/white
2. Irregular outline
3. Widely distributed
4. Enlarge and coallesce


What complications can happen and thus create a complicated plaques?

1. Thrombosis
2. Haemorrhage into the plaque
3. Calcification (can see on X-ray)
4. Aneurysm formation


Where are common sites for atheroma?

1. Aorta - especially abdominal
2. Coronary arteries
3. Carotid arteries
4. Cerebral arteries
5. Leg arteries


Describe the normal structure of an artery, from deep to superficial layers:

1. Endothelium
2. Sub-endothelial connective tissue
3. internal elastic lamina
4. Muscular media
5. External elastic lamina
6. Adventitia


What happens to the proportion of elastic tissue in arteries as you move further away from the heart?

Decreases - lower amplitude pressure pulses the further from the heart you go


What are the consequences of disruption of the internal elastic lamina in the later changes of atheroma?

It alters the compliance of arteries - its ability to expand and contract passively in response to pressure changes.


Why is there an ingrowth of blood vessels seen as part of the later changes of atheroma?

Due to the accumulation of lipid and proliferation of smooth muscle cells, new vessels respond by getting into the area that now requires a larger blood supply.


What are the consequences of plaque fissuring in the later changes of atheroma?

It releases material into the blood stream that promotes thrombosis.


What are the effect of age on risk of atheroma?

The risk slowly increases throughout adult life.


What are the effect of gender on risk of atheroma?

Women are relatively protected before the menopause but catch-up after. This is presumably due to a hormonal basis.


Why is hyperlipidaemia a risk factor for atheroma?

High plasma cholesterol associated with atheroma. LDL levels show the most significant association with atheroma, HDL being protective.


What is the function of chylomicrons?

Transport liver from the intestine to the liver


What is the function of VLDL?

Transport lipids from the liver TAGs from the liver to tissues, as TAGs removed becomes LDL.


What is the function of LDL?

It is rich in cholesterol and carries cholesteron to non-liver cells.


What is the function of HDL?

Carries excess cholesterol from tissue back to the liver.


Polymorphisms of the genes involved in Apoliprotein E are associated with changes in LDL levels and are risk markers for atheroma. Why do they affect LDL levels?

Liver LDL receptor has a high affinity for ApoE. These mutation may affect LDL uptake into the liver and therefore increase in the [LDL] in the circulation and therefore increase the risk of atheroma.


What are physical signs that are associated with familial hyperlipidaemia?

Corneal arcus, tendon xanthoma, xanthelasma


What is the cause of familial hyperlipidaemia?

Genetically determined abnormalities of lipoproteins which lead to the development of atheroma.


What are some proposed mechanisms for the increased risk of ischaemic heart disease that is associated with smoking?

The mode of action is uncertain:
1. Coagulation system affected
2. Reduced prostacyclin - inhibits platelet aggregation and also a vasodilator
3. Increased platelet aggregation


What is the proposed mechanism for the association between IHD and hypertension?

The mechanism is uncertain but may be due to the raised blood pressure causing endothelial damage.


What is the proposed mechanism for the association between IHD and diabetes mellitus - which doubles the IHD risk?

May be related to the hyperlipidaemia and hypertension found in many diabetic patients. DM is also associated with cerebrovascular and peripheral vascular disease.


What quantity of alcohol consumption a day is associated with an increased risk of IHD?

>5 units/day


What infections may be linked with an increased risk of atheroma?

Chlamydia pneumoniae
Helicobacter pylori


What may be the mechanism behind genetic predisposition to atheroma?

1. Variations in apoliprotein metabolism
2. Variations in apoliprotein receptors


What is the thrombogenic theory behind atheroma formation?

This theory is that plaques are formed by repeated thrombi from which the lipid is derived. This is then covered by a fibrous cap.


What is the insudation theory behind atheroma formation?

This theory is that endothelial injury causes inflammation which increases the permeability of the blood vessels to lipid from the plasma.


What is the reaction to injury hypothesis?

1. Plaques form in response to endothelial injury
2. Hypercholesterolaemia leads to endothelial damage in experimental animals
3. Injury increases permeability and allows platelet adhesion
4. Monocytes penetrate endothelium due to changes in permeability
5. Smooth muscle cells proliferate and migrate
(LDL, especially oxidised, may damage endothelium.)


What is the monoclonal hypothesis?

The idea that each plaque is monoclonal and might represent abnormal growth control of smooth muscle. E.g. benign tumour. It proposes that atheroma could have a viral aetiology.
This theory is still not resolved.


List the processes involved in atheroma:

1. Thrombosis
2. Lipid accumulation
3. Production of extracellular matrix
4. Interactions between cell types


How are endothelial cells involved in atheroma formation?

1. Key role in haemostasis
2. Altered permeability to lipoproteins
3. Production of collagen
4. Stimulation of proliferation and migration of smooth muscle cells


How are platelets involved in atheroma formation?

1. Key role in haemostasis
2. Stimulate proliferation and migration of smooth muscle cells (PDGF)


What is the function of PDGF?

PDGF is a potent mitogen for cells of mesenchymal origin: fibroblasts, smooth muscle cells, glial cells etc...


How are smooth muscle cells involved in atheroma formation?

1. Take up LDL and other lipid to become foam cells
2. Synthesis collagen and proteoglycans (which are present in excess in atherosclerotic plaques -> tissue modification)


How are macrophages involved in atheroma formation?

1. Oxidise LDL
2. Take up lipids to become foam cells
3. Secreted proteases which modify matrix
4. Stimulate proliferation and migration of smooth muscle cells


How are lymphocytes involved in atheroma formation?

1. TNF (cytokine) may affect lipoprotein metabolism
2. Stimulate proliferation and migration of smooth muscle cells


How are neutrophils involved in atheroma formation?

Secrete proteases leading to contined local damage and inflammation - these digest the EXM and soften up the atherschlerotic plaque.