Lecture 9 Flashcards
Define atheroma
The accumulation of intracellular and extracellular lipid in the intima of large and medium sized arteries
How long does atherosclerosis take to develop?
Several years
When can atherosclerosis start?
As early as infancy and childhood and progresses very slowly during life
The accumulation of what results in the formation of atherosclerosis? (4)
- lipid
- connective tissue
- inflammatory cells
- smooth muscle cells
What does the Greek work atheros mean?
Gruel or paste
What does the Greek work sclerosis mean?
Hardness
Where can atheromas form? (5)
- Intimal lining of large and medium sized arteries such as the aorta and its branches
- The coronary arteries
- The large vessels that supply the brain
- Carotid arteries
- Leg arteries
How is atherosclerosis detected?
- Typically asymptomatic
- Usually found after a heart attack or stroke
- ## Measure of LDL in blood as a predictor
What are the three layers of the artery?
- Intima
- Media
- Adventitia
What layer of the artery contributes most to its mechanical strength?
The medial layer
What are the macroscopic features of an atheroma?
- Fatty streak
- Simple fibrous plaque
- Complicated plaque
What is a fatty streak?
Compromises a slightly elevated zone on the arterial wall caused by accumulation of a small number of lipid laden cells
What is a simple fibrous plaque?
- Lipid accumulated both free and in cells
- Smooth muscle cells also migrate from the media
- Fibrosis develops around the lipid and forms a cap over the lesion
What is a compliacated plaque?
Ulcers and fissures of the fibrous cap expose plaque contents resulting in thrombosis
What is the development of atherosclerosis initiated by?
Endothelial dysfunction
What are the main components of plaque? (3)
- Lipid containing macrophages
- Extracellular matrix
- Proliferating smooth muscle cells
Where is cholesterol absorbed?
Intestine
Where is cholesterol produced?
Liver
What is the daily cholesterol dietary intake?
300mg
How much cholesterol is synthesized per day?
1 gram
How is cholesterol carried in the blood?
Attached to proteins called lipoproteins
What are the two forms of lipoproteins?
- Low density lipoproteins
- High density lipoproteins
How is LDL removed from the circulation
- By LDL receptor or
- By scavenger cells such as monocytes or macrophages
How is 70% of LDL removed?
By receptor dependent pathway
Where are 75% of LDL receptors located?
On hepatocytes
Give examples of scavenger cells?
- Monocytes
- Macrophages
What do scavenger cells do?
Have receptors that bind LDL that has been oxidized or chemically modified
What is the amount of LDL that is removed by the scavenger pathway directly related to?
Plasma cholesterol level
What causes an increase in the amount of LDL removed by scavenger cells?
- When LDL levels exceed receptor availability
- When there’s a decrease in LDL receptors
How does oxidized LDL form?
When LDL particles react with free radicals
What causes an increase in oxidized LDL levels?
- Consuming a diet high in trans fats
- Smoking
- Poorly controlled diabetes
What cells absorb oxidised LDL?
Specialised white blood cells - macrophages and T lymphocytes
How is a foam cell formed?
When macrophages and lymphocytes absorb oxided LDL
What causes the plaque to rupture?
When the foam cells are not able to process the oxidised LDL and recruit HDL particles to remove the fats
What does LDL in the endothelial lining promote the accumulation of in blood vessels?
- White blood cells (lymphocytes)
- Immune cells (dendritic cells)
- Inflammatory cells (macrophages)
What causes the hardness of the plaques?
Platelets which stick to areas of inflammation in the artery
What is extra cellular matrix?
- Elastin
- Collagen
- Proteoglycans
What causes a plaque to grow further?
Macrophages release growth factors and recruit smooth muscle cells to the plaque. The smooth muscle cells may proliferate and deposit extracellular matrix in the lesions
What forms a cap around a plaque?
Smooth muscle cells
What is released from necrotic foam cells?
Lipids
What do lipids form?
The lipid core of unstable plaques
What does calcium tissue synthesis determine?
- Stiffness
- Calcium fixation
- further ulceration of atheromatous plaque
What drugs are secondary prevention for atherosclerosis?
- Antiplatelets
- Statins
- B blockers
- Ace inhibitors
What drugs are used to control symptoms of atherosclerosis?
- B blockers
- Calcium antagonists
- Nitrates
- Potassium channel openers
- Ranolazine
What surgery can be done for atherosclerosis?
- Bypass
- PCI
What does endothelium damage promote?
Thrombus formation
What does endothelial damage following blood vessel injury result in?
- Loss of the endothelium anti thrombotic functions
- Gain of procoagulant function
What happens when platelets adhere to exposed subendothelial connective tissue ?
Platelets become more spherical and extrude long pseudopods which enhance interaction between adjacent platelets
What do platelets membrane glycoproteins contribute to?
Platelet adhesion to collagen
What allows platelets to bind fibrinogen?
Binding of von willebrand factor results in conformational change within platelet glycoproteins allowing them to bind fibrinogen
What do adherent platelets release?
ADP and thromboxane A2
What are ADP and thromboxane A2?
Platelet agonists
What do ADP and thromboxane A2 do?
Activate more platelets and recruit them to the site of vascular injury
What is the mechanism of action of aspirin?
- Thromboxane A2 is a platelet agonist produced and released by platelets
- Aspirin blocks production of thromboxane A2 by inhibiting platelet enzyme responsible for its synthesis, COX 1
How long does the action of aspirin on platelet COX 1 last?
It’s permanent, lasting for the life of the platelet
How long is the life of a platelet?
7-10 days
What are the lipid lowering drugs?
Statins
When is the greatest cholesterol synthesis?
During fasting states
Which statins have a short half life?
Simvastatin
When is simvastatin usually given?
Before bedtime
