L11: Athersclerosis Flashcards
Define atheroma?
Necrotic core
Consists of dead cells, debris and cholesterol crystals
Define atherosclerosis?
Disease of large and medium sized arteries
Begins in the intima
Plaques accumulate in the artery wall filled with atheromas
Often calcify—> harden
Define arteriolosclerosis?
Hardening of arterioles
Thickening of the walls of the arteries and arterioles
Result of hypertension or diabetes mellitus
Define arteriosclerosis?
Hardening of the arteries
Thickened wall
Reduced elasticity
Includes: Atherosclerosis, arteriolosclerosis, Monkeberg’s disease (uncommon disease, calcification of the media of large arteries)
What are the basic components of an atherosclerotic plaque?
Cells—> macrophages (foam cells), leukocytes (WBCs) and smooth muscle cells
Intra and extracellular lipid
Extracellular matrix—> collagen, elastin and proteoglycans
What are the macroscopic features of atherosclerosis?
Fatty streak
Simple plaque
Complicated plaque
What are the macroscopic features of a fatty streak?
Flat (slightly raised)- no disturbance to blood flow Lipid deposit in intima Foam cells Smooth muscle cells Extracellular lipid
What are the macroscopic features of a simple plaque?
Fatty streak grows
White/yellow
Impinge on lumen of artery
Widely distributed
What are the macroscopic features of a complicated plaque?
- Ulceration—> fibrous cap eroded
- Thrombosis—> exposed plaque thrombogenic, non-exposed can occur, may occlude vessel lumen
- Spasm—> caused by vasoconstrictors released by thrombosis
- Embolism—> exposed atheroma or thrombus
- Calcification—> in and around, makes it hard
- Haemorrhage—> new vessel into plaque, expands plaque causing vessel occlusion or pressure can result in haemorrhage of plaque
- Aneurysm formation—> elastic tissue destroyed by plaque, wall weaker, dilation of wall
- Rupture of atherosclerotic artery—> bleeding, result of weakened media seen in cerebral arteries when patient has hypertension in addition to atherosclerosis
What are the common sites for atherosclerosis formation?
Elastic arteries - Aorta (abdominal) - Carotid - Iliac Large and medium sized muscular arteries - Coronary - Popliteal
- Cerebral
What is the normal arterial structure?
- Endothelium (Tunica Intima)
- Sub-endothelial connective tissue
- Internal elastic membrane/lamina
- Smooth muscle cells and elastic fibres (Tunica Media)
- External elastic lamina
- Connective tissue (Tunica Adventitia)
What are the microscopic changes that appear in the early stags of atherosclerosis formation?
Proliferation of smooth muscle cells
Accumulation of foam cells (macrophages containing lipid)
Extracellular lipid
What are the microscopic changes that appear in the late stags of atherosclerosis formation?
Fibrosis
Necrosis
Cholesterol clefts—> cholesterol crystals
+/- inflammatory cells (different stages of evolution)
Disruption of internal elastic lamina
Damage extends into TM
In growth of BV
Plaque fissuring—> rupture of cap—> bleeding into plaque or thrombosis
What are the clinical effects of atherosclerosis?
Symptoms usually in heart, brain, kidneys, legs or bowel
What are the clinical effects of atherosclerosis on the heart?
Heart—> Ischaemic heart disease, MI, angina pectoris, arrhythmias, cardiac failure,sudden death
What are the clinical effects of atherosclerosis on the brain?
Brain—> cerebral ischaemia, transient ischaemic attack, cerebral infarction (stroke) and mutli-infarct dementia
What are the clinical effects of atherosclerosis on the bowel?
Bowel—> mesenteric ischeamia, ischaemic colitis, malabsorption, intestinal infarction
What are the clinical effects of atherosclerosis on the kidneys?
Kidneys—> hypertension, renal failure
What are the clinical effects of atherosclerosis on the legs?
Legs—> peripheral vascular disease, gangrene
What are the risk factors for athersclerosis?
Non modifiable
- Age
- Gender –> more common in males, incidence increase in famales after menopause
- Genetic predisposition
Modifiable
- Hyperlipidaemia
- Cigarette smoking
- Hypertension
- Obesity
- Georgraphy
- Diabetes Mellitus
- Alcohol
- Infection
How does hyperlipidaemia increase your risk of developing artheresclerosis?
High plasma cholesterol
LDL most significant
LDL delivers cholesterol to peripheral tissue
How are lipids metabolised?
Lipids carried in the blood on lipoproteins
Lipoproteins carry cholesterol and triglycerides
(Hydrophobic lipid core)
Hydrophilic outer layer of phospholipid and apoliopoprotein (A-E)
What are the different types of cholesterol carriers?
Chylomicrons–> lipid from intestine to liver
VLDL–> cholesterol and TG from liver–> TG removed leaving LDL
LDL–> rich in cholesterol, carry cholesterol to non-liver cells
HDL–> carry cholesterol from periphery back to liver
How can genetics affect hyperlipidaemia?
Genetic variation in ApoE associated with changes in LDL levels
At least 6 Apo E phenotypes
What is familial hyperlipidaemia? What are the associated physical signs?
Genetic predisposition
Atherosclerosis at very young age
Signs
–> Corneal Arcus–> ring around the eye
–> Tendon xanthoma–> nodules found in tendon on hand
–> Xanthelasma–> deposit of cholesterol usually around the eye
How does cigarette smoking increase risk of atherosclerosis formation?
Risk factor for ischaemic heart disease
Mode of action uncertain–> coagulation system, reduced PGI2, increased platelet aggregation, increase inflammation, predisposition to oxidation of lipids
How does hypertension increase risk of atherosclerosis formation?
Mechanism unclear
Increase pressure damage BV walls–> predisposes plaque formation
How does diabetes mellitus increase risk of atherosclerosis formation?
Double ischaemic heart disease risk
High risk of cerebral vascular and peripheral vascular disease
Related to hyperlipidaemia and hypertension
How does alcohol consumption increase risk of atherosclerosis formation?
> 5 units per day increased risk
Small amount of alcohol throught to be protective
What are the theories around the pathogenesis of atherosclerosis?
- Thrombogenic theory
- Insudation theory
- Encrustation theory
- Reaction to injury hypothesis
- The monoclonal hypothesis
What is the thrombogenic theory?
Plaques formed by repeated thrombosis
Lipid derived from thrombi
Overlying firbous cap on plaque
What is the insudation theory?
Endothelial injury
Inflammation
Increased permeability to lipid from plasma
What is the encrustation theory?
Model plaques are formed by repeated thrombi overlying thrombi
Lipid core is derived from thrombi
What is the reaction to injury hypothesis?
Chronic inflammatory response of the arterial wall
Hypercholesterolaemia –> endothelial damage
Increases permability–> platelet adhesion
Monocytes penetrate endothelium
SMC proliferate and migrate
Endothelial injury subtle and undetected visually
LDL, especially oxidised may damage endothelium
What is the monoclonal hypothesis?
Crucial role for SMC proliferation
Thought plaques were monoclonal
Therefore atherosclerosis is abnormal growth control
Each plaque benign growth induced by cholesterol or virus
What processes are involved/ appear to be involved?
Thrombosis
Lipid accumulation
Production of intracellular matrix
Interaction between cell types
What are the cells involved?
Endothelial cells Platelets SMC Macrophages Lymphocytes Neutrophils
What role do the endothelial cells play in atherosclerosis formation?
Haemostasis
Altered permeability to lipoproteins
Production of collagen
Stimulation of proliferation and migration of SMC
What role do the platelets play in atherosclerosis?
Haemostasis
Stimulate proliferation and migration of SMC through platelet derived growth factor
What role do the SMC play in atherosclerosis?
Take up LDL–> Foam cells
Synthesis of collagen and proteoglycans
What do the macrophages do in atherosclerosis?
Release free radical–> oxidise LDL
Take up lipids to become foam cells
Secrete proteases which modify the matrix
Stimulate proliferation and migration of SMC
What role do lymphocytes play in atherosclerosis?
Tumour necorsis factor may affect lipid metabolism
Stimulate proliferation and migration of SMC
What do neutrophils do in atherosclerosis?
Secrete proteases leading to continued local damage and infection
What is the unifying hypothesis of how atherosclerosis develops?
- Chronic endothelial insult–> hyperlipidaemia, hypertension, smoking, haemodynamic stress–> endothelial dysfunction
- Platelet adhesion, PDGF release, SMC proliferation and migration
- LDLs (lipid droplets) and monocytes cross endothelium–> accumulated in intima
- LDLs oxidised by free radical released from macrophages
- Macrophages ingest the LDLs –> foam cells
- Crowded foam cells cause the endothelium to bulge
- SMC migrate into the lesion from media and proliferate–> fatty streak
- SMC take up LDL–> foam cells
- SMC secrete collage, elastin and other ECM–> fibrous cap
- Cells in centre die–> necrosis–> dead cells release cholesterol –> cholesterol crystals
- Small BV grow into the adventitia –> plaque undergoes calcification
How can atherosclerosis be prevented?
Decrease total and LDL cholesterol Stop smoking Control hypertension Control weight and regular exercise Sensible alcohol intake Treat diabetes mellitus Anti-oxidants --> Vit E maybe protective
What intervention strategies are there to treat atheroscleoris?
Lipid lowering drugs–> statins, aspirin and prophylaxis
Stop smoking
Modify diet
Treat hypertension
Treat diabetes
Thrombolysis, angioplasty, stents and coronary artery bypass grafts
