Lecture 11 - Atherosclerosis Flashcards
What is Arteriosclerosis?
The thickening of the walls of arteries and arterioles often associated with loss of elasticity
(usually as a result of hypertension or diabetes Mellitus )
What can happen as a result of Arteriosclerosis?
Poor tissue perfusion
Inelastic/weak vessels which can lead to aneurysm
Increased risk of thrombus formation
What is Atherosclerosis?
Accumulation of intracellular and extracellular lipid in the tunica intima and media of medium - large sized arteries
What is an Atheroma?
A necrotic core of the atherosclerotic plaque
The thickening and hardening of arterial walls as as consequence of atherosclerosis
What is contained in the tunica adventitia of blood vessels?
Blood vessels and nerves that supply the vessels
Thick collagen and elastin layer
What are the 2 main events that lead to the development of atherosclerotic plaques?
Endothelial damage
Inflammation
What can lead to endothelial damage?
Hyperlipidaemia (High LDL)
Hypertension
Smoking (toxins)
Haemodynamic stressors
What does Endothelial dysfunction lead to?
Platelet adhesion
Smooth muscle cell proliferation and migration
Lipids (LDL and cholesterol) cross into the tunica Intima
Monocytes (macrophages) cross into intima
What cells end up forming foam cells?
Macrophages
Smooth muscle cells
What is the function of the macrophages when the endothelial wall is damaged?
Secrete cytokines recruiting other inflammatory cells
Stimulate more smooth muscle cells
What is the function of the proliferating/migrating smooth muscle cells when endothelial cells are damaged?
Produce matrix material forming the “roof”
Matrix made of collagen, elastin and other proteins
How do smooth muscle cells migrate when the endothelial cells are damaged?
The endothelial cells (Tunica intima layer) is broken so the smooth muscle cells that reside in the Tunica media can slip into the lumen of the vessel
How do macrophages become foam cells?
How do smooth muscle cells become foam cells?
Macrophages engulf oxidised lipids (like LDL)
SM takes up lipids due to receptors they have
What do the smooth muscle cells in the intima and media begin to produce as they form the fatty streak and as the plaque develops?
Fibrous cap reinforced with collagen and elastin
What does the formation of the fibrous cap by the migrated smooth muscle lead to?
Separates the cells in the centre of the plaque from the blood supply
Leads to a necrotic core developing
What are the cellular components of a necrotic plaque?
Macrophages, leukocytes/white blood cells, smooth muscle cells and platelets
What is the function of endothelial cells in atherosclerotic plaque formation?
Produce collagen
Stimulate the proliferation and migration of smooth muscle cells
What is the function of platelets in atherosclerotic plaque formation?
Stimulates proliferation and migration of smooth muscle cells
What is the function of smooth muscle cells in atherosclerotic plaque formation?
Take up LDL and other lipids becoming foam cells
Make collagen and proteoglycans forming the fibrous cap
What is the function of macrophage in atherosclerotic plaque formation?
Oxidise LDL
Take up this oxidised LDL and become foam cells
Secrete proteases which modify matrix
Stimulates proliferation and migration of smooth muscle cells
What is the function of Lymphocytes in atherosclerotic plaque formation?
Produce TNF which can affect lipoprotein metabolism
Stimulate proliferation and migration of smooth muscle cells
What is the function of neutrophils in atherosclerotic plaque formation?
Secrete proteases leading to continued local damage and inflammation
What is an Intima xanthoma?
Fatty streak
What happens in the development of an atherosclerotic plaque?
Fatty streak (Intima xanthoma)
Fibrous cap atheroma (stable plaque)
Thin fibrous cap atheroma
Now prone to rupture and thrombosis
What happens when the fatty streak forms microscopically?
Proliferation of smooth muscles
Foam cells accumulate
Extracellular lipid
What happens microscopically in the stable simple plaque?
Fibrosis (Fibrous cap)
Necrosis
Inflammatory cells
What happens when the plaque becomes unstable?
Disrupted internal elastic Lamina
New vessels from the Adventitia grow into the plaque
Plaque can erode and ulcerate
How does a fatty streak appear microscopically?
Slightly raised yellow area in the intima
In the blood vessel, where does the fibrous cap form and what is it in contact with?
Forms in contact with the lumen
What is the problem with the fibrous cap of an atheroma being thin?
prone to rupture since its not very strong
Why do unstable plaques usually present as yellow, red and hard?
Yellow from the fatty streaks/thrombosis
Red from the haemorrhaging from the newly formed blood vessels entering the plaques from the advantitia
Hard due to calcification
How does atherosclerosis appear a microscopically?
Narrowed lumen
Different coloured region next to lumen = Fibrous cap
Necrotic core on other side of the fibrous cap
What are the complications of Atherosclerosis?
Ulceration
Thrombosis
Vasospasm (vasoconstriction)
Embolism
Calcification
Haemorrhage
Aneurysm formation
Rupture of atherosclerotic artery
How does ulceration occur in atheroma and what does this lead to?
Fibrous cap becomes thin and breaks
Thrombus can form
How may embolism occur as a result of atherosclerosis?
Bits of the atherosclerotic plaque may break off
How can vessels rupture as a result of atherosclerosis?
Calcification happens making vessels stiffer with less elastic recoil
This can lead to vessels rupturing
What can arterial narrowing and occlusion cause?
Ischaemia
Infarction
It depends on the site and whether there is a lot of collateral circulation
How is haemorrhage caused by atherosclerosis bad?
New vessels grow into the plaque from the adventitia
Bleeding into the plaque narrows the blood vessel since the plaque swells
What affects can atherosclerosis of arteries that lead to the brain have?
Cerebral ischaemia causing:
Transient ischaemic attack
Cerebral infarction = STROKE
Vascular dementia
Cerebral haemorrhage (stroke) due to artheromatous arteries being weaker and hypertensive leading to artery rupture
How can atherosclerosis affect the carotid arteries?
Transient Ischaemic attack (TIA)
Possible embolism of atheromatous deposits to cerebral circulation
How can atherosclerosis affect the heart?
Sudden death
Myocardial infarction
Angina pectoris
Arrhythmias
Cardia failure
The Umbrella term is ischaemic heart disease
What is the difference between stable angina and unstable angina?
stable = pain on exercise
Unstable = pain anytime
If somebody survives a myocardial infarction, why are they likely to develop an arrhythmia?
Fibrous scar tissue replaces the specialised conduction cardiac myocytes
Fibrous scar tissues cant conduct electrical currents as well
What can atherosclerosis of the Mesenteric artery cause?
Mesenteric ischaemia:
Acute Mesenteric ischaemia - intestinal infarction
Chronic Mesenteric ischaemia - Ischaemic colitis can lead to malabsorption
How does a normal bowel visibly differ to an ischaemic bowel?
Ischaemic bowel much darker and very easily broke/perforated when touched
What can be the consequence of atherosclerosis affecting peripheral arteries?
Acute limb ischaemia
Intermittent claudication
Ischaemic rest pain
Gangrene
What are the 6 P’s for Acute and Chronic limb ischaemia?
Pain
Pale/pallor
Perishingly cold
Parasthesia (Tingly)
Paralysis
Pulseless
How can atherosclerosis of the abdominal aorta have further negative affects?
Rupture of Abdominal aortic atheromatous material can lead to an embolus (Can cause acute limb ischaemia)
Can lead to Aneurysmal formation, due to calcification once the artery expands it cant recoil so it stays enlarged
Thrombosis
What risk factors increase the risk of atherosclerosis?
Age
Gender
Hyperlipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus
Alcohol
Infection
Obesity
Lack of exercise
How does gender increase the risk of atherosclerosis?
Women protected quite well before menopause
Men more affected than women
What are the 2 main contributors of Hyperlipidaemia that is key to atherosclerosis?
Cholesterol
LDL (Longest half life of lipoproteins)
What is the general structure of a lipoprotein?
Hydrophobic lipid core
Hydrophilic outer layer of phospholipids and apolipoproteins
What is the very helpful lipoprotein particle and why?
HDL
Removes cholesterol from cholesterol laden tissues to the liver to be metabolised
What affect do the Apolipoprotein defects ApoA1 deficiency /variants have?
Absent/reduced HDL
What happens if there is a defect in the Lipoprotein lipase enzyme?
What is the function of Lipoprotein Lipase?
Type 1 Hyperlipidaemia
Breaks down the TAG contained in a lipoprotein releasing it as fatty acids
What effect does a defect in the LDL receptors cause?
Elevated LDL levels
What is Famililal Hyperlipidaemia?
Genetic abnormalities of lipoproteins which can lead to early development of atherosclerosis
What are the associated signs of familial Hyperlipidaemia?
Corneal arcus
Tendon Xanthomas
Xanthelasma
What is a Xanthelasma?
Fatty deposits around the eye
How can you help treat familial Hyperlipidaemia?
Decrease total cholesterol and LDL in the diet
Lipid lowering drugs (Statins
Low fat and high fibre diet
Aspirin
Why is smoking likely to increase chances of ischaemic heart disease?
Likely makes blood more coagulable
Increased platelet activation
What is the likely mechanism that hypertension increases risk of atherosclerosis?
Endothelial cell damage as a result of the raised pressure allows migration of smooth muscle cells
How can atherosclerosis lead to an aortic /arterial aneurysm?
Calcification leads to the vessels losing their elasticity
Once expanded via systole its difficult for them to return to their original size
What can help reduce the burden of atherosclerosis??
Statins
Anti-hypertensives
Exercise
Normal BMI
Non mover
Alcohol (in moderation)
Diabetic medication
Why does LDL have the longest half life making it more likely to get oxidised leading to the formation of foam cells, fatty streaks then atherosclerotic plaques?
Does not have the peripheral Apolipoproteins ApoC and ApoE
So doesn’t bind to ApoC and ApoE receptors and the liver
So it takes longer for receptor mediated endocytosis
