Lecture 20: Atherosclerosis Flashcards
What is atherosclerosis?
A disease affecting innermost layer of large and medium sized arteries
How many deaths does atherosclerosis contribute in the western world?
> 50%
What does atherosclerosis appear as?
Thickenings called plaques
What are plaques?
Deposits of fibrous tissues and lipids
What is the difference between arteriosclerosis and atherosclerosis ?
Arteriosclerosis is the general term for hardening of arteries
Atherosclerosis is a type of arteriosclerosis
What does atherosclerosis affect?
Arteries
How many layers does an arterial wall consist of?
Three layers
What is the inner most layer called?
Tunica intima
What is the middle layer called?
Tunica media
What is the outer layer called?
Tunica adventitia
Where do the plaques causing atherosclerosis form?
In the tunica intima
What makes up the tunica intima?
Tunica intima consists of Endothelial cells lying on a basement membrane
What are endothelial cells?
Flattened cells separated by tight junctions
What is the function of endothelial cells?
Many functions Containment of blood Selective transport of fluids, gases, ions and proteins into tissues Control of clotting Control of blood pressure
What does the tunica media consist of?
Two layers of elastic laminae with vascular smooth muscle cells in between them
What are vascular smooth muscle cells?
Fascinating cells which contract to regulate vessel diameter
And regulate function and fate of other cells in the vessel wall by secreting cytokines and growth factors
They also lay down extracellular matrix.
What does the tunica adventitia consist of.
Connective tissue
Why do different cell types within vessel walls have to continually communicate
So they can regulate one another’s state and function
What does the exact structure of arteries depend on?
Their size.
Large arteries like aorta and carotid are exposed to high pulsatile pressures so they have prominent elastic laminae hence called elastic arteries
Medium sized arteries like coronary arteries are classified as muscular arteries as their media is composed largely of smooth muscle cells.
What are the four major positive risk factors for atherosclerosis?
Hyperlipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus
What are the other additional positive risk factors for atherosclerosis?
Advancing age Family history Make gender High saturated fat diet Stressful sedentary lifestyles Obesity Excess alcohol consumption Low birth weight Low socioeconomic status Infections - chlamydia organisms
What are the three main negative risk factors of atherosclerosis ?
High levels of circulating HDLP (high density lipoproteins)
Moderate alcohol consumption (2 units per day)
Cardiovascular fitness
Why are lipoproteins important?
They are powerful risk modifiers for atherosclerosis
What are lipoproteins?
They consist of a lipid core (e.g. Triglycerides, cholesterol, cholesterol esters, phospholipids) surrounded by a protein coat
What are the proteins in the protein coat of lipoproteins called?
Apolipoproteins
Why are lipoproteins risk modifiers?
High density lipoproteins are the good type of cholesterol that take lipids away from the liver, therefore they lower the risk of atherosclerosis
What does the initiation of atherosclerosis involve?
Endothelial cell knjury
What is the progression of atherosclerosis following initial EC injury an example of?
Chronic inflammation
Outline the pathogenesis of atherosclerosis?
Endothelial cell injury
Leukocyte migration
Smooth muscle cell activation and migration
Lipoprotein filtration
What is atherogenesis?
The pathogenesis of atherosclerosis
What can endothelial cell injury be caused by?
A combination of
Haemodynamic force of blood (hypertension, branch points)
Chemical insults (cigarette smoke, lipids)
Cytokines
What can damage of endothelial cells lead to?
Altered permeability, > lipid infiltration
Adhesion of leukocytes (due to enhanced expression of chemokines and adhesion molecules)
Activation of thrombosis
What is leukocyte migration into the anterosclerotic plague a type of?
Chronic inflammation which is a hallmark of atherosclerosis
What do circulating monocytes on other leukocyte types adhere to? And what do they enter?
Endothelial cells. They enter the atherosclerotic leison
What happens when circulating monocytes and other leukocyte types enter the atherosclerotic leison?
They ingest large amounts of oxidised lipoproteins
This gives them a foamy appearance
They are called foam cells
What other cells also play an important role?
T lymphocytes and dendritic cells
Recently, what have neutrophils and mast cells been for to perform?
Important functions during atherogenesis
Which cells produce growth factors that activate vascular smooth muscle cells?
Macrophages, platelets, and endothelial cells
What do smooth muscle cells do once activated by growth factors?
Proliferate and migrate from tunica media to the tunica intima
What is the migration of smooth muscle cells into the tunica intima likely to be caused by?
Damage or incomplete development of internal elastic lamina.
But this is not certain
What other roles do smooth muscle cells play in atherosclerotic plaques?
They lay down extracellular matrix which contributes to a fibrous cap
This may later be degraded by matrix degrading protease enzymes
Vascular smooth muscle cells also ingest lipids, and interact with other cell types in the plaque through adhesion molecules present on their surface and growth factors which they secrete.
What happens to lipoproteins in plaques?
They become oxidised
What do oxidised lipoproteins attract?
Monocytes and stimulate several cell types in the plaque to release cytokines and growth factors,
What do the oxidised lipoproteins cause?
Dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells
What do these changes (EC cell injury, leukocyte migration, smooth muscle cell activation and migration, lipoprotein infiltration) together result in ?
A spectrum of leisons
Which leisons are clinically silent?
Type I initial lesion in isolated macrophage foam cells
Type II fatty streak lesion mainly due to intracellular lipid accumulation
Type III intermediate lesion due to type II changes and small extracellular lipid pools
What are the clinically silent or overt lesions?
Type Iv atheroma lesion due to type II changes and core of extracellular lipid
Type V fibroatheroma lesion due to lipid core and fibrotic layer or multiple lipid cores and fibrotic layers, or mainly calcific or mainly fibrotic
Type VI complicated lesion due to surface defect, hematoma-haemorrhage, thrombus
What are the types of lesions in sequence progression?
Type I initial lesion
Type II fatty streak lesion
Type III intermediate lesion
Type IV atheroma lesion (can lead straight to type VI complicated leison)
Type V fibroatheroma lesion
Type VI complicated lesion
What do lesion type I, II, III and IV have in common?
They are all grown mainly by lipid accumulation
What is type V lesion’s main growth mechanism?
accelerated smooth muscle and collagen increase
What is type VI lesion’s main growth mechanism?
Thrombosis, hematoma
Which types of lesions occur from first decade?
Type I and type II
Which types of lesions occur from third decade?
Type III and type Iv
What types of lesions occur from the fourth decade?
Type V and type VI
What does the fibrous cap of an atheroma lesion consist of?
Smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularisation
What does the necrotic centre of an atheroma lesion contain?
Cell debridement cholesterol crystal sum foam cell am calcium
What are the consequences of atherosclerosis?
Atheroma often silent due to pre-clinical phase until sudden onset of symptoms (due to rupture haemorrhage or thrombosis)
Common clinical consequences of atherosclerosis:
Myocardial infarction, peripheral vascular disease, and cerebrovascular disease
