Lesson 6 Flashcards
What does atherosclerosis effect?
• A disease of LARGE arteries
- and of MEDIUM size arteries
- Coronary
- Renal
- Cerebral
- Mesenteric
- Popliteal
Define atherosclerosis
The thickening, narrowing and hardening of the walls of large and medium sized arteries as a consequence of atheroma
Define atheroma
– Greek for ‘porridge’
– An accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
Define arteriosclerosis
The thickening and hardening of the walls of arteries and arterioles – from any cause
What is the normal arterial structure from inside to out (transverse)?
Endothelium Internal elastic lamina Media External elastic lamina Adventitia
What is the macroscopic appearance of atherosclerosis?
• Fundamental lesion is the plaque
• Occur in large elastic arteries (e.g., aorta, carotid, iliac) and medium sized muscular arteries (e.g., coronary, popliteal)
• Plaques develop through three chronological stages:
1. Fatty streak
2. Simple plaque
3. Complicated plaque
What is a ‘fatty streak’?
- Can be seen in children
- First studied in Vietnam USA soldiers
- Lipid deposits in intima
- Yellow, slightly raised
- No disturbance to blood flow
- Relationship to later clinical atheroma somewhat debatable
Describe simple plaque
- Raised yellow/white
- Approximately 1cm in diameter
- Irregular outline
- Widely distributed
- Often occur around ostia
- Turbulent blood flow
- Enlarge and coalesce
- Impinge on vessel lumen
Describe complicated plaque
- Calcification
- Thrombosis
- Haemorrhage into plaque
- In aorta particularly:
- Weakening of the wall
- Aneurysm formation
Describe the macroscopic appearance of atherosclerosis during the early stages
•Early changes: –Accumulation of foam cells –Proliferation of smooth muscle cells –Extracellular lipid deposition –Scattered T lymphocytes
Describe the macroscopic appearance of atherosclerosis during the later stages
•Later changes: –Fibrosis –Necrosis –Cholesterol clefts –Calcification –Disruption of internal elastic lamina –Damage extends into media –Ingrowth of blood vessels –Plaque fissuring & rupture
What are the common sites for atherosclerosis?
- Aorta - especially abdominal aorta
- Coronary arteries
- Carotid arteries
- Cerebral arteries
- Arteries of the legs
•Symptoms usually occur in heart, brain, kidneys and legs
State the four major patterns of atherosclerosis disease
- HEART – coronary arteries – ischaemic damage
- BRAIN – cerebral arteries - stroke
- AORTA – subdiaphragmatic part – aneurysm rupture
- PERIPHERAL ARTERIES – mainly the legs – distal gangrene
Describe the effect atherosclerosis in causing ischaemic heart disease
• Atherosclerosis of coronary arteries reduces blood flow to myocardium.
• Possible consequences: – Myocardialinfarction – Anginapectoris – Chronic congestive cardiac failure (CHF) – Sudden death from arrythmia
What are the mechanisms of ischaemic heart disease?
- Acute severe coronary obstruction
- ACUTE MYOCARDIAL INFARCTION
- Chronic obstruction plus excess demand on heart
- ANGINA PECTORIS
- Chronic obstruction with multiple small infarct damage accumulation
- CHRONIC HEART FAILURE
- Old infarct scar triggering acute LV arrhythmia
- SUDDEN CARDIAC DEATH
Describe acute coronary artery obstruction due to acute thrombosis
- Flow in artery not significantly affected until lumen is reduced by 70- 80% = <1mm diameter
- Coronary thrombosis usually occurs over ruptured atheromatous plaques resulting in myocardial infarction
Explain what the effects of atherosclerosis are when they cause cerebral ischaemia
• Stroke:
–Atherosclerosis of carotid arteries
–Thrombus forms over plaque
–Thromboembolism to cerebral arteries
- Transient ischaemic attack
- Cerebral infarction (stroke)
- Multi-infarct dementia
Explain the impact of complicated atheromatous plaque
• Rupture, ulceration or erosion of the luminal surface of the plaque
–Exposes highly thrombogenic substances -> induce thrombus formation
–Discharges debris into blood = microemboli (cholesterol emboli)
• Haemorrhage into plaque + plaque rupture
• Superimposed thrombus usually on disrupted lesions – may
occlude lumen
• Aneurysmal dilatation – secondary to loss of elastic tissue -> weakness + possible rupture
Explain the impact of abdominal aortic aneurysm (effects of atherosclerosis)
- Aneurysm = local dilatation of an artery -> weakening of wall
- In large arteries almost always due to atherosclerosis
- Can be 10-15cm in diameter
- Lined/filled by thrombus
- May rupture
- Can produce emboli
Explain the impact of peripheral vascular disease (effects of atherosclerosis)
- Intermittent claudication
- Ischaemic rest pain
- Gangrene
- Leriche syndrome
•Particular association with diabetes
Explain the impact of mesenteric ischaemia and bowel infarction (effects of atherosclerosis)
- Superior mesenteric artery disease
- Ischaemic colitis
- Malabsorption
- Intestinal infarction
Explain pathogenesis of atheroma
•Until 1970s, too much lipid in blood passing passively into artery lining
- Now - Reaction to Injury hypothesis:
- Atherogenesis becomes an inflammatory, macrophage and smooth muscle cell response process, involving both lipid/absorbed thrombus on the intima or arteries
What are 5 cellular events that lead to atherosclerosis?
- Chronic endothelial injury
- Endothelial dysfunction
- Smooth muscle emigration from media into intima
- Macrophages + smooth muscle cells engulf accumulated, oxidised lipid -> form foam cells
- Smooth muscle proliferation in response to cytokines and growth factors, collagen and matrix deposition, neovascularistaion
Explain chronic endothelial injury in more depth? (Cellular Events Leading to Atherosclerosis)
- Raised low density lipoprotein (LDL)
- ‘Toxins’ e.g., cigarette smoke
- Hypertension
- Haemodynamic stress
Explain endothelial dysfunction (Cellular Events Leading to
Atherosclerosis)
- Platelet adhesion + release of platelet derived growth factor (PDGF)
- Monocyte accumulation within intima with release of growth factors/cytokines
- T lymphocytes attracted to area
What cells are involved in atherogenesis?
- Endothelial cells
- Platelets
- Smooth muscle cells
- Macrophages
- Lymphocytes
- Neutrophils
What is the effect of plaque rupture from within the artery?
Exposure of tissue triggers both the intrinsic & extrinsic coagulation pathways
Describe what endothelial cells do in atherogenesis
–Key role in haemostasis
–Altered permeability to lipoproteins
–Secretion of collagen
–Stimulate proliferation and migration of smooth muscle cells
Explain what platelets do in atherogenesis
–Key role in haemostasis
–Stimulate proliferation + migration of smooth muscle cells (PDGF)
Explain what smooth muscle cells do in atherogenesis
–Take up LDL and other lipids to become foam cells
–Synthesise collagen and proteoglycans
Explain what macrophages do in atherogenesis
–Oxidise LDL
–Take up lipids to become foam cells
–Secrete proteases which modify matrix
–Stimulate proliferation and migration of smooth muscle cells
What can endothelial injury be due to?
–raised LDL –‘toxins’ eg cigarette smoke –Hypertension –haemodynamic stress –Turbulent blood flow, around branching of arteries
What are some causes of endothelial injury?
–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
–Local thrombosis
Give a brief explanation on atherogenesis mechanisms (3)
•Stimulated SMC produce matrix material •Foam cells secrete cytokines causing –further SMC stimulation –recruitment of other inflammatory cells –ie auto-accelerating process
What are risk factors of atherosclerosis?
–Age (non-modifiable) –Gender (non-modifiable) –Hyperlipidaemia –Smoking –Hypertension –Impaired glucose tolerance and diabetes mellitus –Alcohol –Geography – CIVILISATION & DIET
Why is age a non-modifiable risk factor?
–Slowly progressive throughout adult life
–Risk factors operate over years
Why is gender a non-modifiable risk factor?
–Women relatively protected before menopause
–Presumed hormonal basis
–Incidence in women equals that of men by 70s to 80s
Explain why Hyperlipidaemia and familial hyperlipidaemia are risk factors of atherosclerosis?
–High plasma cholesterol associated with atherosclerosis
–LDL most significant
–High density lipoprotein (HDL) protective
–Homozygous familial hypercholesterolaemia
• Myocardial infarction before 20 years
• Defects in LDL receptor resulting in decreased hepatic uptake of LDL and increased circulating LDL
Explain lipid metabolism
- Lipid in the blood is carried in lipoproteins
- Lipoproteins carry cholesterol and triglycerides (TG)
- Hydrophobic lipid core
- Hydrophilic outer layer of phospholipid and apolipoprotein (A-E)
What is the purpose of chylomicrons in lipid metabolism?
Transport lipid from intestine to liver
What is the purpose of chylomicrons in lipid metabolism?
–Carry cholesterol and TG from liver to muscle and fat
–TG removed leaving LDL
What is the purpose of LDL in lipid metabolism?
–Rich in cholesterol
–Carry cholesterol to non-liver cells
What is the purpose of HDL in lipid metabolism?
–Carry cholesterol from periphery back to liver
Explain the function of IDL and LDL metabolism
- Primary function of LDL is to provide cholesterol from liver to peripheral tissues.
- Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis.
- Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (Liver LDL-Receptor has a high affinity for apoE).
Explain the clinical relevance of IDL and LDL metabolism
- Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative damage.
- Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques.
Describe HDL metabolism
- Reverse cholesterol transport
- HDL can remove cholesterol from cholesterol-laden cells -> return it to the liver
- Important process for blood vessels - reduces likelihood of foam cell + atherosclerotic plaque formation
- ABCA1 protein within cell facilitates transfer of cholesterol to HDL.
- Cholesterol -> cholesterol ester by Lecithin–cholesterol acyltransferase (LCAT)
Where/who is atherosclerosis more prominent in?
–Ubiquitous among developed nations, lower incidence in South America, Africa and Asia
–But South East Asians are predisposed
–And it all depends on social circumstances + diet
–Migrants who immigrate to high risk locations and adopt new lifestyles and diet have the same risk as previously seen in their new location
What is the impact of familial hyperlipidaemia?
–Genetically determined abnormalities of lipoproteins
–Lead to early development of atherosclerosis
–Associated physical signs:
•Corneal arcus
•Tendon xanthomas
• Xanthelasma
Explain the impact of smoking on the development atherosclerosis
– Risk factor for ischaemic heart disease and atherosclerosis
– Risk falls after giving up smoking
– Mode of action uncertain -> procoagulant
• Reduced prostacyclin (which is a platelet activation inhibitor) -> increased platelet aggregation
Explain the impact of hypertension on the development atherosclerosis
–Strong link between ischaemic heart disease and high systolic and diastolic blood pressure
–Mechanism uncertain:
•Perhaps endothelial damage caused by raised pressure
Explain the impact of impaired glucose intolerance and diabetes mellitus on the development atherosclerosis
–Cardiovascular disease accounts for 80% deaths in DM type 2
–DM patients have at least 3 times greater incidence of death from CVD compared to non-DM
–Protective effect in premenopausal women if diabetic
–Diabetes mellitus associated with high risk of cerebrovascular and peripheral vascular disease
Explain the impact of alcohol on the development atherosclerosis
– 5+ units/day associated with increased risk of ischaemic heart disease
–Alcohol consumption, associated with other risk factors, e.g., smoking and high BP, but still an independent risk factor
–Smaller amounts of alcohol may be protective (increase HDL levels)
What are some other risk factors (that have not been mentioned) of atherosclerosis?
–Lack of exercise
–Obesity (produces hypertension, diabetes mellitus, hypertriglyceridaemia and reduced HDL)
–Soft water
–Oral contraceptive pill
–Possibly stress and personality type (type ‘A’)
What are some methods of prevention/interventions for atherosclerosis?
- No smoking
- Decrease fat intake
- Treat hypertension
- Aspirin
- Sensible alcohol intake
- Regular exercise and control of weight control
- Good glycaemic control in diabetes mellitus
- Lipid lowering drugs, e.g., statins, where needed
Atherosclerosis summary
- Major disease of arteries related in large part to age and hyperlipidaemia
- Leads to stenosis of arterial lumen
- No similar change in veins
- The biggest killer in the Western world (myocardial infarctions and strokes)
- Plaque formation takes many years -> silent disease
- When symptoms occur it may be too late to do anything about it as it is not reversible
- Progression may be slowed + complications reduced
What is the purpose of lymphocytes and neutrophils in atherogenesis?
• Lymphocytes:
–TNF may affect lipoprotein metabolism
–Stimulate proliferation and migration of smooth muscle cells
• Neutrophils:
–Secrete proteases leading to continued local damage/ inflammation
