Lecture 20: Atherosclerosis Flashcards
Define atherosclerosis:
Atherosclerosis is a disease affecting the innermost layer of large and medium sized arteries
- It appears as focal thickenings called plaques
Arteriosclerosis is a general term for hardening of arteries - atherosclerosis is a form of this.
What are plaques made up of?
Fibrous tissues and lipids
What are the 3 concentric layers of a vessel wall?
Tunica Intima
Tunica Media
Tunica Externa
Describe the tunica intima:
- Endothelial cells seperated by tight junctions
- Scattered myointimal cells
- Basement membrane
Describe the tunica media:
Smooth muscle cell layers
- Regulate flow by contraction
- Stabilise EC by secreting ECM and activating TGF-beta
Elastic lamina layers
Describe tunica externa (Adventitia)
Connective tissue
Contains
- Fibroblasts
- Leucocytes
- Nerves
- Lymphatics
- Blood vessels (Vasa vasorum) (Too thick for diffusion)
Describe how the size of the tunica media depends on the artery size and how function changes the constituents
Muscular artieres = Lots of smooth muscle
large elastic arteries = Mainly elastic laminae in their media. (recoil, exposed to high pressures)
What sort of system are vessel walls and what happens in atherosclerosis?
Vessel walls are multi-cellular systems and in atherosclerosis the system malfunctions
What is the aetiology of atherosclerosis?
- Positive risk factors increase risk
- Negative risk factors decrease risk
- Now now there is a possible contribution from mutations
What are the positive risk factors for atherosclerosis?
- Hyperlipidemia (esp. inc. cholesterol)
- Cig smoking
- Hypertension (higher shear / wall stress)
- Diabetes mellitus
What are negative risk factors for atherosclerosis?
- High levels of circulating HDL
- Moderate levels of alcohol (uncertain)
- Cardiovascular fitness
What happens with risk factors in terms of disease risk?
They are mulpilicative i.e synergistic
What is the pathogenesis of atherosclerosis?
Uncertain but;
- Initial endothelial cell injury
- Progression involves most components of the cell wall i.e is a process of chronic inflammation
Endothelial cell injury is thought to be one of the most important initiators of atherosclerosis, what might it be the combination of?
- Heamodynamic force i.e shear/stress
- Chemical insults (smoking, lipids)
- Cytokines
What can increased heamocydnamic load, chemical insults and cytokines lead to on endothelial cells?
Hint: PLTR
Plaque Leads To Risk
- Altered permeability (therefore lipid infiltration)
- Adhesion of leucocytes (Due to enhanced expression of chemokines and adhesion molecules)-> Inflammation
- Activation of thrombosis
- Recruitment of endothelial progenitors
Describe the process of foam cell formation in atherosclerotic lesions
Hint: Circulating Monocytes
Chronic inflam
- Circulating monocytes adhere to endothelial cells and enter the atherosclerotic lesion
- These differentiate into macrophages
- Once in the plaque they ingest large amounts of oxidised lipoproteins which gives them the foamy appearance, hence called foam cells.
- When they die by necrosis or apoptosis their cytoplasmic contents (including digested lipids) escape into the extracellular space
EVERY CELL TYPE FOUND TO BE INVOLVED
How does clonal hematopoiesis come into play with atherosclerosis?
- Clonal heamatopoiesis of indeterminate potential (CHIP) is an expanded blood cell ‘clone’ carrying somatic mutation in patient with no other hematological abnormality.
- Accumulates with age
- 1.9x more likely to have CAD
What cells release factors that activate smooth muscle and How are smooth muscles involved in atherosclerosis?
- Macrophages, platelets and endothelial cells produce growth factors that activate vascular smooth muscle cells. (potentially infection too)
- Once activated they proliferate and migrate into the tunica intimate from media.
- This may be accelerated by failure of the internal elastic lamina
How does lipoprotein entry and oxidation influence atherosclerosis? What do they attract and stimulate?
- Lipoproteins become oxidised in plaques
- Oxidised lipoproteins;
- > Attract monocytes
- > Stimulate intra-plaque cells to release cytokines and growth factors
- > These cause dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells
Describe the diagramatic atheroma lesion:
Fibrous cap:
- SM, Macros, Foam cells, Collagen, elastin, lymphocytes)
Necrotic center
- Cell debris, cholesterol crystals (cholesterol clefts), foam cells, calcium
When do plaques become unstable?
- Thin fibrous cap
- High lipid content score
- Inflammation
When do plaques cause symptoms?
When they cause:
- Rupture
- Heamorrhage
- Thrombosis
- Dissection
What are vulnerable plaques characterised by?
Vulnerable plaques are characterised by high lipid and high inflammatory cells content, low content of vascular smooth muscle cells and collagen
What are the common clinical consequences of atherosclerosis?
- MI
- Peripheral vascular disease
- Cerebrovascular disease ie strokes
