Atherosclerosis and heart disease

Question 1

What are the modifiable risk factors of heart disease?

Answer 1

• Smoking
• Lipids intake
• Blood pressure
• Diabetes
• Obesity
• Sedentary lifestyle.

Question 2

What are the non-modifiable risk factors of heart disease?

Answer 2

Age, sex and genetic background

Question 3

What three factors when combined increase heart disease risk exponentially?

Answer 3

1) Smoking
2) Hypertension
3) High cholesterol

Question 4

What happens to low density lipoproteins once deposited in the subintimal space?

Answer 4

Binds to matrix proteoglycans and becomes oxidised by reactive oxygen species released by macrophages

Question 5

What is the step of atherosclerosis?

Answer 5

Coronary artery at lesion-prone location (adaptive thickening of smooth muscle)

Question 6

What is a type II lesion?

Answer 6

Macrophage transmigration into the subendothelial space, phagocytosis oxidised lipoproteins forming foam cells.

Question 7

What is a type III lesion?

Answer 7

Preatheroma: Small pools of extracellular lipid

Question 8

What is a type IV lesion?

Answer 8

Atheroma - core of extracellular lipid forms

Question 9

What is a type V lesion?

Answer 9

Fibroatheroma, progressive fibrosis; thickening the fibrous cap; separating the lipid core from the lumen

Question 10

What is a complicated lesion?

Answer 10

Fissure and haematoma and thrombus formation

Question 11

How do complications arise due to plaque formation?

Answer 11

Due to extensive growth of the lipid cores, narrowing the lumen (stenosis or plaque ruptures)

Question 12

When is the window of opportunity for primary prevention?

Answer 12

Intermediate and advanced lesions

Life-style changes
Risk factor management

Question 13

What is the intervention of arterial stenosis?

Answer 13

Balloon angioplasty PCI

Question 14

What is the function of vascular endothelial cells?

Answer 14

Barrier function (to lipoproteins)

Leukocyte recruitment

Question 15

What is the function of monocytes/macrophages?

Answer 15

Foam cell formation

Cytokine and growth factor release

Major source of free radicals

Metalloproteinases

Question 16

What is the function of vascular smooth muscle cells?

Answer 16

Migration and proliferation within the tunica media

Collagen synthesis

Remodelling and fibrous cap formation

Question 17

What is the function of platelets?

Answer 17

Thrombus generation - presents in acute MI, and unstable angina

Cytokine and growth factor release

Question 18

What is the function of T-lymphocyte?

Answer 18

Macrophage activation

Question 19

Which type of treatment during clinical trials had fewer major adverse cardiovascular events (MACE)?

Answer 19

Anti-Il-1 treatment

Question 20

Which CD macrophage lysosome protein is brown-dyed when associated wot an antibody?

Answer 20

CD68

Question 21

How are macrophage subtypes regulated?

Answer 21

Combination of transcription factors binding to regulatory sequences of DNA

Question 22

What is the main function of inflammatory macrophages?

Answer 22

Phagocytose pathogens

Question 23

What are the three classes of resident macrophages?

Answer 23

Alveolar resident macrophages

Osteoclasts

Spleen (reticuloendothelial)

Question 24

Where are LDLs synthesised?

Answer 24

Within the liver

Question 25

What do LDLs transport?

Answer 25

Cholesterol

Question 26

Where is cholesterol abnormally deposited?

Answer 26

Arterial intima

Question 27

What are the docking molecules that assist with lipid binding?

Answer 27

Apoproteins

Question 28

What are contained within LDL micelles?

Answer 28

Cholesterol esters

Question 29

Which class of lipoproteins transport cholesterol from the peripheral tissues (arteries) to the liver?

Answer 29

High-density lipoproteins (HDLs) -reverse cholesterol transport

Question 30

What type of transporter are HDLs involved in?

Answer 30

Reverse cholesterol transport

Question 31

How are LDLs oxidised?

Answer 31

Free radicals are released by activated macrophages

Question 32

What is the fate of cholesterol within the sub-endothelial space?

Answer 32

Binds to proteoglycans and ultimately oxidised

Question 33

What extracellular matrix protein binds to cholesterol in the sub-endothelial space?

Answer 33

Proteoglycan

Question 34

How does proteoglycan-cholesterol binding influence oxidation?

Answer 34

Increases the susceptibility to modification

Question 35

What is familial hyperlipidaemia?

Answer 35

An autosomal disorder that impairs lipoprotein metabolism by down-regulating LDL receptor expression

Question 36

What is the effect of the down-regulation of LDL receptors?

Answer 36

Diminishes the clearance of LDLs from the plasma Massively elevated cholesterol (20mmol/L) Excessive production of VLDLs .

Question 37

Which type of protein is retained within the sub-endothelial space in FH?

Answer 37

Apolipoprotein B-100 Retained due to interactions with the extracellular matrix. Therefore, this allows reactive oxygen species to modify the surface phospholipids and unesterified cholesterol.

Question 38

How are circulating LDLs ingested in FH?

Answer 38

By unregulated scavenger receptors

Question 39

What are the presentations of FH?

Answer 39

Xanthomas and atherosclerosis

Question 40

What is a xanthoma?

Answer 40

Yellow plaques that occur predominantly besides the inner canthus of the eyelide

Question 41

How is cholesterol regulated?

Answer 41

Negatively regulated by cellular cholesterol (LDL-receptors are sensitive to extracellular serum cholesterol), and are present on the cell surface membrane of hepatocytes

Question 42

Which receptors are sensitive to extracellular serum cholesterol?

Answer 42

LDL receptors

Question 43

What can be deduced by the fact that in LDL-R negative patients, macrophages continued to accumulate cholesterol?

Answer 43

The presence of scavenger receptors - that are unresponsive to negative feedback facilitated by the continued intake of oxidised LDL.

Question 44

What are the functions of macrophage scavenger receptor A (CD204)?

Answer 44

Binds to oxidised LDL Binds to gram positive bacteria (staphylococci and streptococci) Binds to dead cells

Question 45

Which type of macrophage scavenger receptor binds to malaria parasites?

Answer 45

MSRB (CD-36)

Question 46

What are the functions of macrophage scavenger receptor B?

Answer 46

* Binds to oxidised LDL * Binds to malaria parasites * Binds to dead cells.

Question 47

Which oxidative enzymes are released by macrophages, that can modify native LDL?

Answer 47

NADPH oxidase (superoxide O2) Myeloperoxidase

Question 48

Which types of molecules are upregulated by IL-1?

Answer 48

VCAM-I Vascular cell adhesion molecule-1

Question 49

What is the function of VCAM-I?

Answer 49

Mediates tight monocyte binding involves in recruitment

Question 50

Which type of chemokine is released by activated macrophages that recruits monocyte?

Answer 50

Monocyte chemotactic protein-I MCP-I

Question 51

Which type of receptors does MCP-I bind onto?

Answer 51

Monocyte G-protein coupled receptor CCR2

Question 52

What are the effects of macrophage derived growth factors?

Answer 52

Recruit vascular smooth muscle and promote proliferation to deposit extracellular matrix.

Question 53

Which types of growth factors are released by macrophages?

Answer 53

1) Platelet derived growth factor (PDGF) | 2) Transforming growth factor beta (TGF-b)

Question 54

What is the function of PDGF?

Answer 54

Support VSMC chemotaxis, survival and promote cell division.

Question 55

What is the function of TGF-b?

Answer 55

Increases collagen synthesis and matrix deposition.

Question 56

What is the effect on VSMCs by interactions of PDGF and TGF-b?

Answer 56

Contractile smooth conversion to synthetic atherosclerotic cells with reduced contractile filaments and an increase in matrix deposition genes

Question 57

What are the two differences between normal medial contractile and synthetic atherosclerotic cells?

Answer 57

Decreased contractile filaments And increase in matrix deposition genes (In Synthetic)

Question 58

Which type of proteinases are released by macrophages?

Answer 58

Metalloproteinases

Question 59

What is the function of metalloproteinases released by macrophages?

Answer 59

Responsible for forming a proteolytic cascade to degrade collagen, requiring zinc in the active site

Question 60

Which ion is involved in metalloproteinases?

Answer 60

Zinc

Question 61

What are the impacts of metalloproteinases on the fibrous cap?

Answer 61

Potentiates thin fibrous cap degradation, increasing the susceptibility of plaque rupture Rupture promotes coagulation - occlusive thrombus and cessation of blood flow

Question 62

What is the consequence of a thin fibrous cap rupture by metalloproteinase activity?

Answer 62

Causes the release of necrotic foam debris into the arterial lumen, this initiates thrombosis that ultimately causes an infarction

Question 63

Which OxLDL derived metabolite is toxic?

Answer 63

7-keto-cholesterol

Question 64

Which transcription factor regulates inflammation and is activated by numerous inflammatory stimuli?

Answer 64

Nuclear kappa B

Question 65

Which receptors are expressed by nuclear kappa B?

Answer 65

Scavenger receptors Toll-like receptors Cytokine receptors (IL-1)

Question 66

Nuclear kapp B activates the gene expression of what in macrophages?

Answer 66

MMPs, Inducible nitric oxide synthase and interleukin - implicated in inflammation

Question 67

What are the risk factors of athersclerosis?

Answer 67

``` Smoking Hypertension Diabetes Hyperlipidemia Localised disturbed flow ```