Atherosclerosis

Question 1

what is atheroma?

Answer 1

accumulatiob of intracellular and extracellular lipid in the intima of large and medium sized arteries

Question 2

when will partial occulusion in an artery have clinical consequence?

Answer 2

during physical activity when there is more requirement for oxygen (can lead to angina and require GTN to dilate the arteries to improve blood flow)

Question 3

what is atherosclerosis?

Answer 3

the tickening and harderning of arterial walls as a consquence of atheroma in large and medium sized arteries

Question 4

what is arteriosclerosis?

Answer 4

develops with age and is to do with elasticity of vessels

Question 5

what does atherosclerosis result from?

Answer 5

Accumulation of lipid, connective tissue, inflammatory cells and smooth muscle cells in the intima

Question 6

what are the three layers of an artery?

Answer 6

Adventitia
Media
Intima

Question 7

what happens when plque in vessels crack?

Answer 7

ruptures blood vessels and leads to intraplaque haemorrhage causing bleeding and can result in clots

Question 8

where is common sites for atherosclerosis to occur?

Answer 8

• aorta
• coronary arteries
• carotid arteries
• cerebral arteries
• leg arteries (usually femoral arteries)

Question 9

how is atherosclerosis detected?

Answer 9

• typically asymptomatic
• most often found after manifests itself such as heart attack or stroke
• measure of total blood cholesterol is most important along with LDL

Question 10

what does the intima of the artery release?

Answer 10

nitric oxide
prostacyclin
bradykinin

Question 11

what is the adventitia of an artery?

Answer 11

fibrous with elastin and collagen

Question 12

what layer of an artery contributes to the mechanical strangth?

Answer 12

medial layer

Question 13

what are the stages of plaque formation?

Answer 13

• starts with damage to the endothelium (trauma)
• lipids are circulating and oxidative stress is high due to post translational modification
  -LDL becomes oxidated and taken up by cells and scavenger receptors and taken up into tissue
• fatty streak form due to invasion, LDL is recognised from the macrophages as foreign and engulfs

Question 14

what is simple (fibrous) plaque?

Answer 14

• lipid accumulation, both free and in cells. smooth muslce cells also migrate from the media
• Fibrosis develops around the lipid and forms a cap over the lesion

Question 15

what is complicated plaque?

Answer 15

ulcers and fissures of the fibrous cap expose plque contents, resulting in thrombosis

Question 16

what is fibrosis?

Answer 16

loss of elasticity (inert tissue)

Question 17

what is the hypothesis for atherosclerosis development?

Answer 17

response to injury initiated by endothelial dysfunction

Question 18

what are the main components of plaque?

Answer 18

lipid containing macrophages
extracellular matrix
cells, proliferating smooth muscle cells

Question 19

what happens when macrophage engulfs lipid?

Answer 19

complex develops the foam part of the plaque

Question 20

where is cholesterol resynthesised?

Answer 20

in the liver by HMG coA reductase

Question 21

where does statins work?

Answer 21

HMG coA reductase enzyme

Question 22

what is cholesterol carried in the blood by?

Answer 22

lipoproteins LDL and HDL

Question 23

how does oxidised LDL form?

Answer 23

when LDL particles react with free radicals

Question 24

what increases oxidised LDL?

Answer 24

consuming a diet high in trans fat
smoking
poorly controlled diabetes

Question 25

what plays a role in the pathogenesis of atherosclerotic lesions?

Answer 25

LDL with its high cholesterol content - mechanical stress such as that associated with hypertension - products associated with smoking - immune mechanims

Question 26

why is there electrostatic adherance of endothelial cells?

Answer 26

endothelial cells are negativelty charged and so are platelets (held by tight junctions)

Question 27

what happens to tight junctions when LDL is oxidised?

Answer 27

loss of tight junction increases permeability allowing elements to come in contact with immune cells and diapedesis occurs

Question 28

what do macrophages release for plaque to grow further?

Answer 28

- growth factors that recruit smooth muscle cells to the plaque - SMC may proliferate and deposit extracellular matrix in the lesions (elastin, collagen, proteoglycans) and plaque grows further and SMC may form a cap round the plaque

Question 29

what happens to lipids reoleased from necrotic foam cells?

Answer 29

they accumulate to form the lipid core of unstable plaques. connective tissue synthesis setermines stiffness, calcium fixation and further ulceration of atheromateous plaque

Question 30

what is phenolytic modulation?

Answer 30

process where SMC cells change their structure, function and biochemical characteristics in response to environmental stimuli or injury

Question 31

what is the prevention of atheroma?

Answer 31

- no smoking - diet - reduce fat intake, diet high in fruits and vegatables decreases risk of CVD and death - not too much alcohol - regular exercise

Question 32

what are examples of endogenous antiplatets?

Answer 32

ADPase prostacyclin nitric oxide

Question 33

what are endogenous anticoagulants?

Answer 33

- heparin like molecules (active antithrombin III) - thrombomodulin (activates protein C - protein S

Question 34

what is an example of a fibrinolytic and what does it prevent?

Answer 34

tissue-type plaminogen activator (prevents blood clots from growing

Question 35

what procoagulants is found in damaged endothelium

Answer 35

- production of vWF - production of tissue factor - binding of factors IXa and Xa

Question 36

what is the platelets function of adhesion?

Answer 36

- following injury there is a loss in antithrombic function and a gain of procoagulant function - platelets adhere to exposed connective tissues and become more spherical and extrude long pseudopods which enhances interactiob between adjacent platelets

Question 37

what contributes to platelet adhesion to collagen?

Answer 37

platelet membrane glycoproteins

Question 38

what does the binding of von willbrand factor result in?

Answer 38

conformational changes within platelet glycoproteins allowing platelts to bind fibrinogen allowing the molecules to interconnect the platelets serving as the basis for platelet aggregation

Question 39

what causes blood to clot?

Answer 39

ADP and blood

Question 40

what do adherance platelets release?

Answer 40

ADP and thromboxane A2 - platelet agonists which activate more platelets and recruit them to the site of vascular injury

Question 41

what are common anti-platelet drugs?

Answer 41

aspirin clopidegrel ticagrelor

Question 42

how does aspirin work?

Answer 42

blocks production of thromboxane A2 by inhibiting the platelet enzyme COX-1 which is responsible for the synthesis of thromboxane A2

Question 43

how does clopidegrel work?

Answer 43

is an irreversible inhibitor of ADP receptor on platlets (P2y12 receptors) and so prevents ADP from activating platelets

Question 44

how does tigagrelor work?

Answer 44

potent antiplatelet agent that reversibly bind and inhibits the P2Y12 receptor on platelet and is direct-acting

Question 45

when is cholesterol production the greatest?

Answer 45

at night - this is why simvastatin has to be taken at night as it has a short half life

Question 46

what are off target effects of statins?

Answer 46

anti-inflammatory antiplatelet improves NO function anti-proliferative could reduce BP

Question 47

what are stains inhibitors of?

Answer 47

HMG coA reductase, inhibits the synthesis of cholesterol