Athlerosclerosis Flashcards
Define atherosclerosis
Atherosclerosis is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries.
The thickening and hardening of arterial walls as a consequence of atheroma
Define arteriosclerosis
The thickening of the walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus
What are the macroscopic features of atherosclerosis?
Fatty streak
Simple plaque
Complicated plaque
What is a fatty streak?
Lipid deposits in intima
Yellow, slightly raised
Relationship to atherosclerosis somewhat debatable but, seen as precursors for it.
What is a simple plaque?
raised yellow / white
Irregular outline
Widely distribute
Enlarge and coalesce
What is a complicated plaque?
Thrombosis
Haemorrhage into plaque
Calcification - Can see on x-rays
Aneurysm formation - expansion of artery
What are some common sites of atherosclerosis?
- Aorta - particularly abdominal (renal and could go into iliac)
- Coronary arteries
- Carotid arteries
- Cerebral arteries
- Leg arteries
What is normal arterial structure?
- Endothelium
- Sub-endothelial CT
- Internal elastic lamina (closer to heart, more elastic and muscle)
- Muscular media
- External elastic lamina
- Adventitia
Microscopic features of atherosclerosis (early changes)
Early changes:
- Proliferation of smooth muscle cells
- Accumulation of foam cells
- Extracellular lipid
Microscopic features of atherosclerosis (later changes)
Later changes:
- Fibrosis
- Necrosis
- Cholesterol clefts - where cholesterol was
- +/- inflammatory cells
- Disruption of internal elastic lamina
- Damage extends into media
- Ingrowth of blood vessels - leaky, can lead to haemorrhage
- Plaque fissuring
What are the clinical effects of atherosclerosis?
- Ischaemic heart disease
- Sudden death
- Myocardial infarction
- Angina pectoris (chest pain on exertion - goes away when rested)
- Arrhythmias
- Cardiac failure - due to fibrosis.
- Manifest as shortness of breath and pulmonary oedema.
What are the clinical effects of athlerosclerosis in the brain?
Cerebral ischaemia
- Transient ischaemic attach (TIA - mini stroke as resolve in 24hrs)
- Cerebral infarction (stroke) - thrombus in cerebral artery or thromboembolus
- Multi-infarct dementia
Clinical effects of atherosclerosis of the bowel
Mesenteric ischaemia
- Ischaemic colitis
- Malabsorption
- Intestinal infarction
What are the clinical effects of peripheral vascular disease?
- Arms are rare so usually legs
- Intermittent claudication - distance can walk before pain in calf.
- Leriche syndrome (blockage of abdominal aorta as it goes to common iliac arteries.)
- Ischaemic rest pain - when worse
- Gangrene - once tissue has infarcted.
Why do people get athleroscleosis?
- Age - slowly progressive throughout adult life. Risk factors operate over years
- Gender - males more affected than females as women are protected relatively before menopause. There is a presumed hormonal basis
- Hyperlipidaemia
- Cigarette smoking
- Hypertension
- Diabetes mellitus
- Alcohol
- Infection
Why does hyperlipidaemia cause athlerosclerosis?
- High plasma cholesterol associated with athlerosclerosis
- LDL most significant
- HDL protective
Lipid metabolism
- Lipid in the blood is carried on lipoproteins
- Lipoproteins carry cholestrol and triglycerides (TG)
- Hydrophobic lipid core
- Hydrophilic outer later of phospholipid and apolipoprotein (A-E)
- Chylomicrons - Transport lipid from intestine to liver
- LDL - Rich in cholestrol and carries to choletrol to non-liver cells.
- VLDL - Carry cholestrol and TG to liver. TG removed leaving LDL.
- HDL - Carry cholestrol from periphery back to liver
Apolipoprotein E
- Genetic variations in Apo E are associated with changes in LDL levels
- Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes.
- Polymorphisms can be used as risk markers for atherosclerosis
Familial Hyperlipidaemia
Genetically determined abnormalities of lipoproteins
Lead to early development of atherosclerosis
Associated physical signs:
- Arcus (A thin, whitish circle around the iris; normal finding in old people.)
- Tendon xanthoma (deposits of cholestrol)
- xanthelasma (depositions of cholestrol)
How does cigarette smoking cause atherosclerosis?
- Don’t know - effect coagulation system, reduced Prostaglanin I2, Incresed platelet aggregation.
- Powerful risk factor for IHD
- Risk falls after giving up.
Hypertension and atherosclerosis
- Strong link between IHD and high systolic / diastolic BP
- Mechanism uncertain
- Maybe endothelial damage caused by raised pressure.
Atherosclerosis and diabetes Mellitus
- DM doubles IHD risk.
- Protective effect in premenopausal women lost
- DM also associated with high risk of carebrovascular and peripheral vascular disease
- It is maybe related to hylerlipidaemia?
Atherosclerosis - Alcohol Consumption
Over 5 units per day is associated with increased risk of IHD
Alcohol consumption after associated with other risk factors e.g. smoking and high BP but still an independent risk factor.
Smaller amounts of alcohol may be protective.
Atherosclerosis-Infection
- Chlamydia pneumoniae
- Helicobacter pylori
- Cyromegalovirus
All look at but no hard evidence.
Atherosclerosis - Other Risk Factors
- Lack of exercise
- Obesity
- Soft water
- Oral contraceptives
- Stress and personality type?
Atherosclerosis - Genetic Predisposition
Familial predisposition well known
Possibly due to:
- variations in apolipoprotein metabolism
- variations in apolipoprotein receptors
What are the theories as to how atherosclerosis develops?
- Thrombogenic theory
- Isudation theory - Movement from lumen into the wall
- Monoclonal hypothesis
- Reaction to injury hypothesis
The thrombogenic theory of atherosclerosis
Though that plagues formed by repeated thrombi.
Lipids derived from thrombi
Overlying fibrous cap.
Insudation theory of atherosclerosis
Endothelial injury causes inflammation.
This makes the vessel leaky and allows lipid from the plasma into wall and develop.
Reaction to injury hypothesis
Plaques form in response to endothelial injury
Hypercholestrolaemia leads to endothelial damage in experimental animals
Injury increases permeability and allows platelet adhesion.
Monocytes penetrate endothelium
Smooth muscle cells proliferate and migrate.
Endothelial injury may be very subtle and be undetectable visually.
LDL, especially oxidised, may damage endothelium.
The monoclonal hypothesis
Aside, not widely accepted
Crucial role for smooth muscle proliferation
Each plaque is monoclonal
Might represent abnormal growth control
What are the stages of atherosclerosis?
Thrombosis
Lipid accumulation
Production of intercellular matrix
Interactions between cell types
What cells are involved in atherosclerosis?
Endothelial cells
Platelets
Smooth muscle cells (become foam cells)
Macrophages
Lymphocytes
Neutrophils
Endothelial cells in Atherosclerosis
Key role in haemostasis
Altered permeability to lipoproteins
Production of collagen
Stimulation of proliferation and migration of smooth muscle cells.
Platelets in atherosclerosis
Key role in haemostasis
Stimulate proliferation and migration of smooth muscle cells (PDGF - platelet derived growth factor)
Smooth muscle cells in atherosclerosis
Take up LDL and other lipid to become foam cells
Synthesise collagen and proteoglycans
Macrophages in atherosclerosis
Oxidise LDL
Take up lipids to become foam cells
Secrete proteases which modify matrix
Stimulate proliferation and migration of smooth muscle cells.
Lymphocytes in atherosclerosis
TNF May affect lipoprotein metabolism. Stimulate proliferation and migration of smooth muscle cells.
Neutrophils in atherosclerosis
Secrete proteases leading to continued local damage and inflammation
What causes endothelial injury?
Endothelial injury due to:
Raised LDL
‘Toxins; e.g. cigarette smoke.
Hypertension
Haemodynamic stress
What are the consequences of endothelial injury?
Endothelial injury causes:
Platelet adhesion, PDGF release, SMC proliferation and migration
Insudation of lipid, LDL, oxidation, uptake of lipid by SMC and macrophages
Migration of monocytes into intima
What are final things cause atherosclerosis?
Stimulated SMC (smooth muscle cells) produce matrix material
Foam cells secrete cytokines causing:
- Further SMC stimulation
- Recruitment of other inflammatory cells
How do you prevent atherosclerosis?
No smoking
Reduce fat intake (ish.. not matter too much if good fat metabolism)
Treat hypertension
Not too much alcohol
Regular exercise / weight control
BUT, some people will still develop atherosclerosis!
What interventions can reduce the risk of atherosclerosis?
- Stop smoking
- Modify diet
- Treat hypertension
- Treat diabetes
- Lipid lowering drugs
