Lecture 9 - atherosclerosis

Question 1

what is atheroma?

Answer 1

atheroma is the accumulation of intracellular and extracellular lipid in the intimate of large and medium sized arteries

Question 2

what is atherosclerosis ?

Answer 2

the thickening and hardening if arterial walls as a consequence of atheroma in large and medium sized arteries

Question 3

what does atherosclerosis result from?

Answer 3

develops over several decades

it starts as early as infancy and childhood and progresses very slowly during life

it results from accumulation of lipid, connective tissue, inflammatory cells, and smooth muscle cells in the intima

Question 4

where does atherosclerosis occur?

Answer 4

primarily in arteries

common sites
- aorta - especially abdominal
- coronary arteries
- carotid arteries
- cerebral arteries
- leg arteries

Question 5

what is the detection of atherosclerosis ?

Answer 5

atherosclerosis is typically asymptomatic

it is most often found after it manifests itself as a heart attack or stroke

measure of low density lipoprotein (LDL) in blood as a predictor

20% of events occur in individuals with no major risk factors

Question 6

what are the macroscopic features of atheroma?

Answer 6

fatty streak - comprises if a slightly elevated zone on the arterial wall caused by accumulation of a small number of lipid lien cells

simple (fibrous) plaque - lipid accumulates, both free and in cells. smooth muscles also migrates from the media. fibrosis develops around the lipid and forms a cap over the lesion

complicated plaque (ulcers and fissures of the fibrous cap expose plaque concepts resulting in thrombosis)

Question 7

what is the current hypothesis of atherosclerosis?

Answer 7

the atherosclerotic process is not fully understood.

current hypothesis is the repose to injury
intimated by endothelial dysfunction

Question 8

what are the main components of the plaque?

Answer 8

lipid containing macrophages

extracellular matrix

cells, proliferating smooth muscle cells

Question 9

what is cholesterol attached to?

Answer 9

cholesterol is carried in the blood attached to proteins called lipoproteins

Question 10

what are the two main forms of lipoproteins?

Answer 10

low density lipoprotein and high density lipoprotein

Question 11

how much LDL is removed by LDL receptors and where are most located?

Answer 11

approximately 70% of LDL is removed by the LDL receptor dependant pathway

LDL are widely distributed but approx 75% are located on hepatocytes; bus liver plays important role in LDL metabolism

Question 12

what are scavenger cells and what do they have that binds to it?

Answer 12

scavenger cells such as monocytes and macrophages have receptors that bind LDL that has been oxidised or chemically modified

Question 13

what is amount of LDL removed by related to?

Answer 13

amount of LDL removed by scavenger pathway is directly related the plasma cholesterol level.

Question 14

what happens when ldl levels exceed receptor availability?

Answer 14

amount of LDL that is removed by scavenger cells is greatly increased

Question 15

how does oxidation of LDL occur?

Answer 15

the oxidation of LDL occurs when the LDL particles react with free radicals

Question 16

what can increase the levels of oxidised LDL?

Answer 16

consuming a diet high in trans fats, smoking and poorly controlled diabetes

Question 17

what does hyperlipidaemia particularly LDL with its high cholesterol content do?

Answer 17

it is believed to play an active role in the pathogenesis of the atherosclerotic lesion

Question 18

what are possible injurious agents in what causes injury to the endothelial cell?

Answer 18

products associated with smoking

immune mechanisms

mechanical stress, such as that associated with hypertension

Question 19

describe the major cellular events in the progression of atheroscelerosis

Answer 19

1. when LDL becomes oxidised, it goes directly into the endothelium and may alter endothelial permeability - increased stiffness
2. monocyte adhesion and transmigration - LDL encourages the accumulation of inflammatory cells, such as monocytes. monocytes transform into macrophages, more macrophages and cholesterol accumulate at the site forming a plaque
3. macrophage transformation into foam cell - as more macrophages and cholesterol accumulate, the oxidised cholesterol loaded macrophage forms ‘foam cell’ and the plaque begins to grow thicker
4. smc migration - macrophage releases growth factors that recruit smooth muscle cells to the plaque. The smooth muscle cells may proliferate and deposit extracellular matrix in the lesion (elastin, collagen, proteoglycans) and the plaque grows further. smooth muscle may form a cap around the plaque

lipids related from neurotic foam cells accumulate to form the lipid core of unstable plaques. connective tissue synthesis determines stiffness, calcium fixation and further ulceration of atheromatous plaque

Question 20

how are smooth cells recruited to the plaque?

Answer 20

smooth muscle phenotypic modulation

smooth cells transform, migrate and phagocytise material.

they appear to take in macrophage-like properties

Question 21

what are the primary prevention actions taken for atheroma treatment?

Answer 21

no smoking

diet - reduce fat intake. a diet high in fruits and veg decreases the risk of cardiovascular disease and death

not too much alcohol

regular exercise and weight control

Question 22

what drugs are used in secondary prevention of atheroma?

Answer 22

antiplatelets and statins

beta blockers

ace inhibitors

Question 23

what drugs are used for the symptoms control in atheroma?

Answer 23

beta blockers

calcium antagonists

nitrates (short and long acting)

potassium channel openers (nicrorandil)

if channel inhibition (ivabridine)

ranolazine

Question 24

what is surgery treatment for atheroma ?

Answer 24

bypass

PCI (Percutaneous coronary intervention (PCI) refers to a family of minimally invasive procedures used to open clogged coronary arteries )

Question 25

what are the platelet functions in normal vs damaged endothelium ?

Answer 25

normal endothelium - antiplatelet, anticoagulant and fibrinolytic

damaged endothelium - procoagulant functions

Question 26

describe the antithrombotic functions

Answer 26

antiplatelet
- adenosine diphsopahtase
- prostacyclin (produced by the enzyme cyclooxyrgenase)
- nitric oxide

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

fibrinolytic (prevents clots from growing
- tPA

Question 27

descrive procoagulant functions

Answer 27

Production of vWF
Production of tissue factor
Binding of factors IXa and Xa

Question 28

describe platelet function - adhesion

Answer 28

Platelets adhere to the exposed subendothelial connective tissues. Following adhesion, platelets become more spherical and extrude long pseudopods which enhance interaction between adjacent platelets.

Platelet membrane glycoproteins contribute to platelet adhesion to collagen. The binding of von Willebrand factor(vWF) results in conformational changes within platelet glycoproteins allowing platelets to bind fibrinogen. Fibrinogen molecules then interconnect the platelets serving as the basis for platelet aggregation.

Question 29

what do adherent platelets release?

Answer 29

ADP and thromboxane A2

Question 30

what are ADP and thromboxane A2 ?

Answer 30

platelet agonists, activate more platelets and recruit them to the site of vascular injury

Question 31

what are antiplatelet drugs?

Answer 31

aspirin

clopidogrel

Question 32

what is the mechanism of action of aspirin ?

Answer 32

thromboxane A2 is a platelet agonist produced and released by platelets.

aspirin blocks production of thromboxane A2 by inhibiting the platelet enzyme responsible for its synthesis - cyclooxygenase-1 (COX-1)

the action of aspirin on platter COX-1 is permanent, lasting for the life of the platelet (7-10 days)

Question 33

describe the mechanism of action of clopidogrel?

Answer 33

ADP is a platelet agonist produced and released by platelets

clopidogrel is an irreversible inhibitor of ADP receptor on platelets and so prevents ADP from activating platelets

Question 34

what are statins used for ?

Answer 34

reduce plasma LDL

statins are HMG-CoA reductase inhibitors so inhibit the synthesis of cholesterol.

cholesterol greatest production at night - statins with shirt half life given at bedtime